tentative report on the safety assessment of the...
TRANSCRIPT
The 2010 Cosmetic Ingredient Review Expert Panel members are: Chairman, Wilma F. Bergfeld, M.D., F.A.C.P.;
Donald V. Belsito, M.D.; Ronald A. Hill, Ph.D; Curtis D. Klaassen, Ph.D.; Daniel Liebler, Ph.D; James G. Marks,
Jr., M.D., Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director
is F. Alan Andersen, Ph.D. This report was prepared by Wilbur Johnson, Jr., Senior Scientific Analyst/Writer.
Co s m e t i c I n g r e d i e n t R e v i e w
1101 17th Street, NW, Suite 412 ♢ Washington, DC 20036-4702 ♢ (202) 331-0651 ♢ [email protected]
Tentative Report on the Safety Assessment of
the Cosmetic Ingredient Review
Expert Panel
On the Safety Assessment of
Pelargonic Acid (aka Nonanoic Acid)
and Nonanoate Esters
April 6, 2010
iii
TABLE OF CONTENTS
ABSTRACT ................................................................................................................................................................... 1
INTRODUCTION .......................................................................................................................................................... 1
CHEMISTRY ................................................................................................................................................................. 2
DEFINITION AND STRUCTURE .................................................................................................................................. 2
CHEMICAL AND PHYSICAL PROPERTIES ................................................................................................................. 2
UV ABSORPTION .......................................................................................................................................................... 2
ANALYTICAL METHODS .............................................................................................................................................. 3
METHODS OF PRODUCTION ..................................................................................................................................... 3
IMPURITIES ................................................................................................................................................................... 3
USE ............................................................................................................................................................................. 3
PURPOSE IN COSMETICS ............................................................................................................................................ 3
SCOPE AND EXTENT OF USE IN COSMETICS .......................................................................................................... 3
NONCOSMETIC USE..................................................................................................................................................... 4
GENERAL BIOLOGY ...................................................................................................................................................... 4
METABOLISM ................................................................................................................................................................ 4 Ethyl Pelargonate ........................................................................................................................................................ 4
PERCUTANEOUS ABSORPTION.................................................................................................................................. 4 Isononyl Alcohol ......................................................................................................................................................... 5
SKIN PENETRATION ENHANCEMENT ....................................................................................................................... 5
ENDOCRINE DISRUPTION .......................................................................................................................................... 5
ANIMAL TOXICOLOGY ................................................................................................................................................. 5
ACUTE INHALATION TOXICITY .................................................................................................................................. 5 Pelargonic Acid ........................................................................................................................................................... 5 Isononanoic Acid ........................................................................................................................................................ 6 Isononyl Alcohol ......................................................................................................................................................... 6
ACUTE ORAL TOXICITY ............................................................................................................................................... 6 Pelargonic Acid ........................................................................................................................................................... 6 Cetearyl Nonanoate ..................................................................................................................................................... 6 Cetearyl Isononanoate ................................................................................................................................................. 6 Isononyl Isononanoate ................................................................................................................................................ 6 Ethyl Pelargonate ........................................................................................................................................................ 7 Ethylhexyl Pelargonate ............................................................................................................................................... 7 Isononyl Alcohol ......................................................................................................................................................... 7 Isotridecyl Alcohol ...................................................................................................................................................... 7 Neopentyl Glycol Diisononanoate .............................................................................................................................. 7 PEG-5 Isononanoate ................................................................................................................................................... 7
iv
Neopentyl Glycol ........................................................................................................................................................ 7
ACUTE DERMAL TOXICITY ......................................................................................................................................... 7 Pelargonic Acid ........................................................................................................................................................... 7 Cetearyl Nonanoate ..................................................................................................................................................... 8 Ethyl Pelargonate ........................................................................................................................................................ 8 Isononyl Alcohol ......................................................................................................................................................... 8 Neopentyl Glycol Diisononanoate .............................................................................................................................. 8
ACUTE INTRAVENOUS TOXICITY .............................................................................................................................. 8
ACUTE INTRAPERITONEAL TOXICITY ...................................................................................................................... 8
SHORT-TERM ORAL TOXICITY ................................................................................................................................... 8 Pelargonic Acid ........................................................................................................................................................... 8 Isononyl Alcohol ....................................................................................................................................................... 10 Neopentyl Glycol ...................................................................................................................................................... 10
SHORT-TERM DERMAL TOXICITY ........................................................................................................................... 10 Pelargonic Acid ......................................................................................................................................................... 10
SUBCHRONIC ORAL TOXICITY ................................................................................................................................. 11 Ethyl Pelargonate ...................................................................................................................................................... 11
OCULAR IRRITATION/TOXICITY .............................................................................................................................. 11 Pelargonic Acid ......................................................................................................................................................... 11 Cetearyl Nonanoate ................................................................................................................................................... 12 Isononyl Isononanoate .............................................................................................................................................. 12 Ethylhexyl Pelargonate ............................................................................................................................................. 12 Neopentyl Glycol Diisononanoate ............................................................................................................................ 12 PEG-5 Isononanoate ................................................................................................................................................. 12 Isononyl Alcohol ....................................................................................................................................................... 12
SKIN IRRITATION ........................................................................................................................................................ 12 Pelargonic Acid ......................................................................................................................................................... 12 Cetearyl Nonanoate ................................................................................................................................................... 13 Cetearyl Isononanoate ............................................................................................................................................... 13 Isononyl Isononanoate .............................................................................................................................................. 13 PEG-5 Isononanoate ................................................................................................................................................. 13 Ethyl Pelargonate ...................................................................................................................................................... 13 Ethylhexyl Pelargonate ............................................................................................................................................. 13 Isononyl Alcohol ....................................................................................................................................................... 14
INFLAMMATION ......................................................................................................................................................... 14
SKIN IRRITATION AND SENSITIZATION .................................................................................................................. 14 Pelargonic Acid ......................................................................................................................................................... 14 Cetearyl Nonanoate ................................................................................................................................................... 15 Neopentyl Glycol Diisononanoate ............................................................................................................................ 16 PEG-5 Isononanoate ................................................................................................................................................. 16
REPRODUCTIVE AND DEVELOPMENTAL TOXICITY ..................................................................................................... 16
Pelargonic Acid ............................................................................................................................................................ 16
Isononyl Alcohol ........................................................................................................................................................... 17
v
Neopentyl Glycol ........................................................................................................................................................... 17
GENOTOXICITY .......................................................................................................................................................... 17
Pelargonic Acid ............................................................................................................................................................ 17
Cetearyl Nonanoate ...................................................................................................................................................... 18
Ethylhexyl Isononanoate ............................................................................................................................................... 18
Neopentyl Glycol Diisononanoate ................................................................................................................................ 18
PEG-5 Isononanoate ..................................................................................................................................................... 18
Neopentyl Glycol .......................................................................................................................................................... 19
Methyl Pelargonate ....................................................................................................................................................... 19
CARCINOGENICITY .................................................................................................................................................... 19
ANTITUMOR ACTIVITY .............................................................................................................................................. 19 Pelargonic Acid ......................................................................................................................................................... 19 Ethyl Pelargonate ...................................................................................................................................................... 20
CLINICAL ASSESSMENT OF SAFETY ............................................................................................................................ 20
SKIN IRRITATION ........................................................................................................................................................ 20 Predictive Tests ......................................................................................................................................................... 20
Pelargonic Acid ..................................................................................................................................................... 20 Cetearyl Nonanoate ............................................................................................................................................... 22 Neopentyl Glycol Diisononanoate ........................................................................................................................ 23 Ethyl Pelargonate .................................................................................................................................................. 23
Provocative Tests ...................................................................................................................................................... 23
SKIN IRRITATION AND SENSITIZATION .................................................................................................................. 23 Predictive Tests ......................................................................................................................................................... 23
Cetearyl Nonanoate ............................................................................................................................................... 23 Ethylhexyl Isononanoate ....................................................................................................................................... 23 Isodecyl Isononanoate ........................................................................................................................................... 24 Isononyl Isononanoate .......................................................................................................................................... 24 Neopentyl Glycol Diisononanoate ........................................................................................................................ 24
SKIN SENSITIZATION ................................................................................................................................................. 24 Predictive Tests ......................................................................................................................................................... 24
Pelargonic Acid ..................................................................................................................................................... 24 Cetearyl Isononanoate ........................................................................................................................................... 24 Cholesteryl Nonanoate .......................................................................................................................................... 25 Isotridecyl Isononanoate ....................................................................................................................................... 25 Isodecyl Isononanoate ........................................................................................................................................... 25 Isononyl Isononanoate .......................................................................................................................................... 25 PEG-5 Isononanoate ............................................................................................................................................. 25 Ethyl Pelargonate .................................................................................................................................................. 25
Provocative Test ........................................................................................................................................................ 25 Isotridecyl Alcohol ................................................................................................................................................ 25
EPIDERMAL PROLIFERATION AND APOPTOSIS ................................................................................................... 25
vi
EFFECT ON CD1a AND ICAM-1 EXPRESSION ........................................................................................................ 26
CASE REPORTS ........................................................................................................................................................... 26 Pelargonic Acid ......................................................................................................................................................... 26 Cetearyl Isononanoate ............................................................................................................................................... 27 Isononyl Isononanoate .............................................................................................................................................. 27
SUMMARY OF INFORMATION FROM EARLIER CIR SAFETY ASSESSMENTS ................................................................ 27
Propylene Glycol Esters and Diesters – including Propylene Glycol Dipelargonate .................................................. 27
Butyl, cetyl, isobutyl, isocetyl, isopropyl, myristyl, and octyl (now ethyhexyl) stearate ............................................... 28
Decyl and Isodecyl Oleate ............................................................................................................................................ 28
SUMMARY ................................................................................................................................................................ 28
DISCUSSION .............................................................................................................................................................. 30
CONCLUSION ............................................................................................................................................................ 31
1
ABSTRACT
Pelargonic Acid and its esters, straight- and branched-chain, are reviewed in this safety assessment. Most of
these ingredients have the skin conditioning agent function in common when used in cosmetic products. In the absence
of percutaneous absorption data on these ingredients using intact skin, the available octanol-water partition coefficient
(logP) and molecular weight data suggest that some would penetrate the skin, whereas others would not. However, the
available data suggest that product formulations containing these ingredients would be non-irritating and non-
sensitizing to human skin. The CIR Expert Panel concluded that these ingredients are safe in the present practices of
use and concentration.
INTRODUCTION
Pelargonic acid (aka nonanoic acid) is a fatty acid that can function as a fragrance ingredient, surfactant-
cleansing agent, and surfactant-emulsifying agent in cosmetics. In its soap form, it can function as a surfactant-
cleansing agent. Many of the fatty acids that are used in cosmetics and their synthesized derivatives (primarily esters
and diesters of the corresponding alcohol and pelargonic acid) have similar additional functions in cosmetics. An
idiosyncrasy in the terminology used in the International Cosmetic Ingredient Dictionary and Handbook is that most of
these derivatives are termed nonanoates, not pelargonates.
This safety assessment includes pelargonic acid and the following esters of pelargonic acid:
pelargonic acid
butylene glycol diisononanoate
cellobiose octanonanoate
cetearyl isononanoate
cetearyl nonanoate
cetyl isononanoate
cholesteryl nonanoate
diethylene glycol diethylhexanoate/diisononanoate
diethylene glycol diisononanoate
dihydrocholesteryl nonanoate
dipentaerythrityl pentaisononanoate
ethylhexyl isononanoate
glycereth-7 diisononanoate
isodecyl isononanoate
isononyl isononanoate
isostearyl isononanoate
isotridecyl isononanoate
neopentyl glycol diisononanoate
PEG-2 diisononanoate
PEG-5 isononanoate
pentaerythrityl tetraisononanoate
phytosteryl nonanoate
polyglyceryl-20 octaisononanoate
propylene glycol diisononanoate
tridecyl isononanoate
ethylhexyl pelargonate
ethyl pelargonate
isobutyl pelargonate
methyl pelargonate
neopentyl glycol dicaprylate/dipelargonate/dicaprate
2
pentaerythrityl tetrapelargonate
The nonanoate or pelargonate esters and diesters are straight-chain compounds, whereas the isononanoate
esters and diesters are branched-chain compounds. Propylene glycol dipelargonate would have been included in this
safety assessment; however, the Cosmetic Ingredient Review (CIR) Expert Panel previously concluded that this
ingredient is safe in the present practices of use in cosmetic products. 1
Pelargonic acid is a reactant in the esterification process that yields all of the esters included in this safety
assessment. While this fatty acid is not reported to be currently used in cosmetics, much of the data available for
review relate to pelargonic acid. The CIR Expert Panel has published safety assessments on the following fatty
alcohols and other reactants used to form some of the esters reviewed in this safety assessment, and other fatty acid
esters: butylene glycol - safe in present practices of use and concentration [safe],2,3
cetearyl, cetyl, and isostearyl
alcohols – safe,4,5
cholesterol – safe,6,3
ethylene glycol – special report on reproductive and developmental toxicity - no
conclusion,7 octyl palmitate – safe,
8,9 PEG-7 glyceryl cocoate – safe as used in rinse-off products; safe up to 10% in
leave-on products,10
PEGs-2 and -6 dilaurate – safe for use in cosmetics at concentrations up to 25%,11
octyl stearate
and isobutyl stearate – safe, 12,5
isodecyl oleate – safe,13,14
and propylene glycol dipelargonate – safe,1 as stated above.
These conclusions may contribute to the safety assessment of ingredients in the current review for which little or no
data have been identified in the published literature.
Similarly, there are ingredient moieties that have not been reviewed by the Expert Panel, and available data on
these chemicals may be useful in the absence of safety test data on some of the esters that are being reviewed. Thus,
data on or relevant to the following chemicals are also summarized in the current safety assessment: isononanoic acid,
isononyl alcohol, isotridecyl alcohol, neopentyl glycol, isobutyl alcohol, and isodecyl alcohol. The summary,
discussion, and conclusion from the CIR Final Safety Assessment on propylene glycol dipelargonate and other
propylene glycol esters and diesters are also included, because these data may be useful in evaluating the safety of
diesters included in the current review. Similarly, these sections from the CIR Final Safety Assessments on isobutyl
stearate and isodecyl oleate are also included, in lieu of data on isobutyl alcohol and isodecyl alcohol, respectively.
CHEMISTRY
DEFINITION AND STRUCTURE
Chemical definitions, other chemical names, and cosmetic ingredient functions for the ingredients reviewed in
the safety assessment are included in Table 1. The International Nomenclature Cosmetic Ingredient (INCI) name
appears first in each series of chemical names; “iso” in a chemical name denotes methyl branching/substitution and
does not necessarily imply substitution on the second carbon atom.15
Chemical structures/formulas are included in
Figure 1. The inclusion of [sic] after a technical name or CAS No. in Table 1 denotes those instances wherein the
authors of the dictionary associated a specific branched chemical entity other than an omega-2 methyl susbstituted
isomer with an “iso” INCI name. According to the dictionary proviso regarding “iso”-named ingredients, all branched
isomers are potentially included by an “iso” INCI ingredient name. For simplicity, only omega-2 isomers are shown
Figure 1. However, in one exception, the [sic] notation was included after “octyl iso-nonanoate,” in the ethylhexyl
isononanoate box of Table 1 to designate that this dictionary technical name is simply wrong.”
CHEMICAL AND PHYSICAL PROPERTIES
Available chemical and physical properties are included in Table 2.
UV ABSORPTION
Data provided by Symrise GmbH & Co.16
indicated that the following chemicals did not absorb significantly
in the 250 to 400 nm range: neopentyl glycol diisononanoate, cetyl nonanoate + stearyl nonanoate, trideceth-9 + PEG-
5-isononanoate + water, glyceryl triisononanoate + glyceryl diisononanoate, and ethylhexyl isononanoate.
3
ANALYTICAL METHODS
Pelargonic acid, cholesteryl nonanoate, ethyl pelargonate, and methyl pelargonate have been analyzed by
nuclear magnetic resonance (NMR), infrared (IR), and mass spectrometry, and pentaerythrityl pelargonate has been
analyzed by IR spectrometry .17
Methyl pelargonate and pelargonic acid have also been analyzed by gas
chromatography-mass spectrometry,18
and the same is true for ethyl pelargonate .19
METHODS OF PRODUCTION
Pelargonic acid is prepared from unsaturated hydrocarbons by the oxo process, by the oxidation of oleic acid,
and from tall oil unsaturated fatty acids and rice bran oil fatty acid.20
IMPURITIES
Specifications on pelargonic acid from a chemical supplier include pelargonic acid (90% minimum), iron (1.0
ppm max), moisture (0.2% max), and the following monobasic acids: C9 (93%), and other monobasic acids (2%).21
USE
PURPOSE IN COSMETICS
The majority of the ingredients reviewed in this safety assessment function as skin conditioning agents in
cosmetics. Cholesteryl nonanoate is the only ingredient for which an ingredient function in cosmetics is not listed in
the International Cosmetic Ingredient Dictionary and Handbook. Ingredient functions in cosmetics are included in
Table 1.15
SCOPE AND EXTENT OF USE IN COSMETICS
According to information supplied to the Food and Drug Administration (FDA) by industry as part of the
Voluntary Cosmetic Registration Program (VCRP) in 2009,22
only the following ingredients reviewed in this safety
assessment are being used in cosmetic products: cetearyl isononanoate, cholesteryl nonanoate, diethylene glycol
diethylhexanoate/diisononanoate, ethylhexyl isononanoate, isodecyl isononanoate, isononyl isononanoate, isotridecyl
isononanoate, tridecyl isononanoate, and ethylhexyl pelargonate. These use data are summarized in Table 3.
Independent of these data, the results of a survey of current ingredient use concentrations that was conducted by the
Personal Care Products Council in 2009 are also summarized in Table 3.23
For example, cetearyl isononanoate is used
in 5 of the 1196 eye shadow products reported to the VCRP, and results from the separate industry survey indicate use
of this ingredient at a concentration of 0.05% in these products. In other cases, for example, uses are reported to the
VCRP, but use concentration data are not available, as for cetearyl isononanoate. Current use concentration data from
the Personal Care Products Council also indicate that, while not reported to the VCRP, the following ingredients are
also being used in cosmetic products: butylene glycol diisononanoate, cetearyl nonanoate, cetyl isononanoate,
dipentaerythrityl pentaisononanoate, neopentyl glycol diisononanoate, PEG-2 diisononanoate, PEG-5 isononanoate,
pentaerythrityl tetraisononanaote, polyglyceryl-20 octaisononanoate, and pentaerythrityl tetrapelargonate.
Table 3 also identifies ingredients that appear to be in use because industry has provided use concentrations,
but for which no uses were reported to the VCRP. For example, cetyl isononanoate has uses reported in 5 product
categories, based on industry data.
Based on the data included in Table 3 (use frequency and use concentration data), there is no indication that
the following ingredients are being used in cosmetics: cellobiose octanonanoate, diethylene glycol diisononanoate,
dihydrocholesteryl nonanoate, glycereth-7 diisononanoate, isostearyl isononanoate, phytosteryl nonanoate, propylene
4
glycol diisononanoate, ethyl pelargonate, isobutyl pelargonate, methyl pelargonate, neopentyl glycol
dicaprylate/dipelargonate/dicaprate, and pelargonic acid.
Cosmetic products containing the in-use ingredients may be applied to the skin or hair, or, incidentally, may
come in contact with the eyes, nails, and mucous membranes. Products containing these ingredients may be applied as
frequently as several times per day and may remain in contact with the skin/hair for variable periods following
application. Daily or occasional use may extend over many years.
NONCOSMETIC USE
Pelargonic acid is included on the list of food additives (synthetic flavoring substances and adjuvants)
permitted for direct addition to food for human consumption, as stated in 21 CFR 172.515.24
According to 21 CFR
173.315,24
an aliphatic acid mixture consisting of valeric, caproic, enanthic, caprylic, and pelargonic acids is approved
for use at a level not to exceed 1% in a lye peeling solution used in the peeling of fruits and vegetables (21 CFR
173.315).24
Another approved use of pelargonic acid relates to sanitizing solutions that may be used safely on food-
processing equipment and utensils, and on other food-contact articles. One such solution contains decanoic acid,
pelargonic acid, phosphoric acid, propionic acid, and sodium 1-octanesulfonate, according to 21CFR 178.1010.24
Pelargonic acid is registered by the United States Environmental Protection Agency (EPA) for use as a
blossom thinner and as an herbicide. 25,26
It is exempt from the requirement of a tolerance for pesticide residues in or on
all foods, when used as a component of a food contact surface sanitizing solution in food handling establishments.27
GENERAL BIOLOGY
METABOLISM
Straight-chain pelargonic acid esters are likely hydrolyzed to component alcohols and pelargonic acid, which
is further metabolized to acetate moieties that enter the citric acid cycle. With the exception of pelargonic acid and
ethyl pelargonate, information on the metabolism of the remaining ingredients reviewed in this safety assessment was
not identified in the published literature. Neither industry nor a search of the published literature provided guidance on
the metabolic fate of branched nonanoate esters, acids, or alcohols.
The oxidative degradation of fatty acids, such as pelargonic acid, into 2-carbon fragments through
enzymatically-catalyzed reactions is a well-documented central metabolic pathway in animals and plants. Pelargonic
acid, a straight-chain carbon molecule, would be metabolized by beta-oxidation to form acetate molecules, which enter
the citric acid cycle and are metabolized to carbon dioxide, water, and energy.25,28
Ethyl Pelargonate
According to Opdyke,29
straight-chain aliphatic acid esters are thought to be readily hydrolyzed into their
component acids and alcohols, which would then be expected to follow their normal metabolic pathways.
PERCUTANEOUS ABSORPTION
Of the logP values included in Table 2, neopentyl glycol (molecular weight [mw] < 500) has a logP of < 1
and values ≥ 3 are reported for the following compounds: pelargonic acid (mw < 500), cellobiose octanonanoate (mw
> 500), cholesteryl nonanoate (mw > 500), ethylhexyl pelargonate (mw < 500), ethyl pelargonate (mw < 500), isobutyl
pelargonate (mw < 500), methyl pelargonate (mw < 500), pentaerythrityl tetrapelargonate (mw > 500), isononanoic
acid (mw < 500), and isononyl alcohol (mw < 500). Compounds with molecular weights greater than 500 (e.g.,
cellobiose octanonanoate and pentaerythrityl tetrapelargonate) are less likely to penetrate the skin. Actual skin
penetration data (rabbits, abraded skin) indicate that isononyl alcohol, under occlusion, is percutaneously absorbed.
5
Isononyl Alcohol
The results of an acute dermal toxicity study30
on undiluted isononyl alcohol (rabbits, abraded skin) are
summarized later in the report text. When the occlusive binders were observed after 24 h of contact in this study,
percutaneous absorption was evident.
SKIN PENETRATION ENHANCEMENT
The skin penetration enhancement effect of pelargonic acid on other chemicals has been demonstrated in vitro
using human stratum corneum and hairless rat skin.
Tanojo and Junginger31
studied the skin penetration enhancement effects of fatty acids on p-aminobenzoic acid
(PABA) penetration through sheets of human stratum corneum (surgically removed human breast or abdominal skin).
The stratum corneum sheet was pre-treated with the penetration enhancer. The permeation of PABA increased with
increasing chain-length of straight-chain saturated fatty acid, from 6 to 9 carbons (hexanoic, heptanoic, octanoic, and
pelargonic acids, respectively). A sharp increase in PABA permeability occurred at fatty acid chain lengths between 8
and 9 carbons. The mean steady state flux for PABA was 837.84 ± 190.30 µg/cm2/h in the presence of pelargonic acid,
compared to 2.57 ± 0.19 µg/cm2/h in the presence of water and 0.28 ± 0.14 µg/cm
2/h in the presence of propylene
glycol.
Kanikkannan et al.32
conducted a study on the release profile of melatonin from drug-in-adhesive type
transdermal patches (prepared using Eudragit® E 100 as adhesive polymer) containing pelargonic acid or other
penetration enhancers, and the in vitro penetration of melatonin through hairless rat skin in the presence of the
enhancer. Melatonin release was studied using the United States Pharmacopoeia dissolution test apparatus in
conjunction with high performance liquid chromatography. The release profiles of melatonin from the patches with
enhancers were similar when compared to the control patch release profile.
In skin penetration experiments, each penetration enhancer was added to the patch at a concentration of 2.5%
or 5%. Skin samples from at least 3 rats were used in each experiment, and each mean value for skin penetration
represented 3 replicates. The presence of enhancers in the patches resulted in an increase in the permeation of
melatonin through hairless rat skin. The mean melatonin flux values for patches containing octanol, pelargonic acid, or
myristic acid (each at both concentrations) were higher when compared to the control patch; however, the differences
were not statistically significant (P > 0.05). Each mean value represented 3 replicates.32
ENDOCRINE DISRUPTION
According to EPA,28
it would be unlikely for straight chain carbon molecules, as in the C9 carbon chain of
pelargonic acid, to be associated with a risk of endocrine disruption.
ANIMAL TOXICOLOGY
ACUTE INHALATION TOXICITY
An acute inhalation LC50 of 1.34 mg/L was reported for pelargonic acid in a study involving rats. Inhalation
exposure to isononanoic acid caused a concentration- dependent decrease in respiratory frequency in mice, and an
RD50 of 420 mg/m3 was reported. Few and no deaths were reported for mice/rats and guinea pigs, respectively,
following inhalation exposure to isononyl alcohol at a concentration of 21.7 mg/L.
Pelargonic Acid
EPA25
placed pelargonic acid in toxicity category III (> 0.5 through 2 mg/liter), primarily based on the results
of the following study. The acute inhalation toxicity of pelargonic acid was evaluated using groups of 10 (5 males, 5
females/group) albino rats .33
The 4 groups were exposed (4-hour exposure) to aerosol generated from undiluted
6
pelargonic acid, delivering concentrations of 0.510, 0.710, 2.20, and 3.31 mg/L, respectively. The following mortalities
were reported: 1 rat (at 0.510 mg/L), 1 rat (at 0.710 mg/L), 8 rats (at 2.20 mg/L), and 10 rats (at 3.31 mg/L). Gross
necropsy was performed on animals that died, and the following findings were considered unusual and possibly related
to exposure: nasal discharge; polyuria; salivation; and discolored and swollen lungs, and variations thereof. Acute
inhalation LC50’s of 0.87 mg/L (95% confidence limits = 0.50 to 1.51 mg/L) and 2.10 mg/L (95% confidence limits =
1.71 to 2.58 mg/L) were reported for males and females respectively. The overall LC50 was 1.24 mg/L (95%
confidence limits undefined).
Isononanoic Acid
Detwiler-Okabayashi34
evaluated the respiratory effects of isononanoic acid using groups of 4 specific
pathogen-free, male Swiss-Webster mice. The animals were exposed to nebulized isononanoic acid (concentration
range: 172 to 755 mg/m3) in a 2.5 l exposure chamber for 180 min. Sensory and pulmonary irritation were reported,
and recovery immediately post-exposure was described as poor. The test substance concentration that was capable of
evoking a 50% decrease in the mean respiratory frequency (RD50) was 420 mg/m3. The decreases in respiratory
frequency induced by isononanoic acid were described as concentration-dependent and due to a combination of sensory
and pulmonary irritation.
Isononyl Alcohol
Scala and Burtis30
35
studied the inhalation toxicity of isononyl alcohol using groups of 10 Swiss mice, Wistar
rats, and English Short Hair guinea pigs. Each group received a single 6-h vapor exposure under dynamic conditions;
exposure was followed by a 14-day observation period. The concentration of isononyl alcohol in the exposure
chamber was calculated to be 21.7 mg/liter. None of the animals died during exposure; however, one mouse and 2 rats
died within the first 14 h post-exposure. Signs of systemic toxicity consisted primarily of central nervous system
depression, but were not pronounced. Local irritation involving mucous membranes of the eyes and nose was observed
to a variable extent, and all animals had recovered within 1 h after termination of exposure. Histopathological
examinations were not performed.
ACUTE ORAL TOXICITY
Pelargonic acid and the esters for which data are available are not significant acute oral toxicants (LD50s >
1 g/kg).
Pelargonic Acid
EPA25
placed pelargonic acid in toxicity category IV (> 5000 mg/kg) , primarily based on the results of the
following study. The acute oral toxicity of nonanoic acid was evaluated using 2 groups of 10 specific-pathogen-free SD
(Crj:CD) rats (5 males, 5 females/group).35
One group was dosed orally with nonanoic acid in corn oil (dose = 5,000
mg/kg). The control group was dosed with vehicle only. None of the animals died and no abnormal clinical signs
were noted during the 14-day observation period. There was no evidence of macroscopic abnormalities at necropsy.
The LD50 was > 5,000 mg/kg, and nonanoic acid was considered nontoxic.
Cetearyl Nonanoate
The acute oral toxicity of cetearyl nonanoate (97% pure) was evaluated using groups of 4 Sprague-Dawley
CD rats.36
One group was dosed orally with 300 mg/kg and the remaining 2 groups were dosed with 2,000 mg/kg.
None of the animals died. Signs of systemic toxicity were observed in the 300 mg/kg dose group, but not in the 2,000
mg/kg dose group. Necropsy did not reveal any abnormal findings, and an LD50 of > 2,000 mg/kg body weight was
reported.
Cetearyl Isononanoate
According to Evonik Industries, 37
an LD50 of > 5,000 mg/kg was reported for cetearyl isononanoate in a
study involving mice. Study details were not provided.
Isononyl Isononanoate
7
According to Evonik Industries ,38
an LD50 of > 5,000 mg/kg was reported for isononyl isononanoate in a
study involving rats. Study details were not provided.
Ethyl Pelargonate
According to Opdyke,29
acute oral LD50 values of > 43,000 mg/kg and 24,190 mg/kg have been reported for
rats and guinea pigs, respectively.
Ethylhexyl Pelargonate
The acute oral toxicity of undiluted ethylhexyl pelargonate was evaluated using 10 albino rats (5 males, 5
females).39
A single oral dose of 5 g/kg body weight was administered to each animal. Dosing was followed by a 14-
day observation period, and gross necropsy was performed on animals that survived. The LD50 was > 5 g/kg.
Isononyl Alcohol
Scala and Burtis30
evaluated the acute oral toxicity of isononyl alcohol using 5 fasted, male Sprague-Dawley
rats. An acute oral LD50 of 2.98 g/kg was reported.
Isotridecyl Alcohol
According to Guilian and Naibin,40
the acute oral LD50 for isotridecyl alcohol in rats is 17,000 mg/kg.
Neopentyl Glycol Diisononanoate
The acute oral toxicity of undiluted neopentyl glycol diisononanoate was evaluated using groups of 4
Sprague-Dawley CD rats.41
One group was dosed orally with 300 mg/kg and the remaining 2 groups were dosed with
2,000 mg/kg. None of the animals died, and there were no signs of systemic toxicity in either of the 3 groups.
Necropsy did not reveal any abnormal findings, and an LD50 of > 2,000 mg/kg body weight was reported.
PEG-5 Isononanoate
The acute oral toxicity of PEG-5 Isononanoate was evaluated using 2 groups of 3 fasted Sprague-Dawley CD
rats.42
Animals of both groups were dosed orally with 2,000 mg/kg. None of the animals died and necropsy did not
reveal any abnormal findings. An LD50 of > 2,500 mg/kg body weight was reported.
Neopentyl Glycol
According to Guilian and Naibin,40
the acute oral LD50 for neopentyl glycol in rats is 3259 mg/kg. The
Organisation for Economic Co-operation and Development (OECD)43
reported an acute oral LD50 of 3200 mg/kg (rats)
for neopentyl glycol.
ACUTE DERMAL TOXICITY
Pelargonic acid and the esters for which data are available are not significant acute dermal toxicants (LD50s
of >2,000 to 9,000 g/kg).
Pelargonic Acid
In a study involving rabbits,29
the acute dermal LD50 was greater than 5 g/kg (number of animals not stated).
EPA25
placed pelargonic acid in toxicity category III (> 2000 through 5000 mg/kg), based on the results of the
following acute dermal toxicity studies that were published in a Federal Register notice:28
The application of pelargonic
acid to intact and abraded skin of mice induced moderate to severe skin irritation, and an acute dermal LD50 of 9000
mg/kg was reported in this study. An acute dermal LD50 of 5000 mg/kg (rabbits) for undiluted pelargonic acid also
has been reported.
8
The acute dermal toxicity of nonanoic acid was evaluated using 2 groups of 10 specific-pathogen-free SD
(Crj:CD) rats (5 males, 5 females/group) .44
The test substance, in deionized water, was placed on filter paper that was
applied to clipped, shaved skin (4 x 5 cm site) of the back for 24 hours. Deionized water (0.5 ml) was applied to control
animals according to the same procedure. None of the animals died during the 21-day observation period. Scales/scabs
in the dorsal region (test substance-related) were observed only in treated females (days 3 to 17 post-application).
Macroscopic abnormalities were not observed in any of the animals (test or controls) at necropsy. It was concluded that
the LD50 for nonanoic acid in males and females was > 2,000 mg/kg.
Cetearyl Nonanoate
The acute dermal toxicity of cetearyl nonanoate (97% pure) was evaluated using 10 Sprague-Dawley CD strain
rats (5 males, 5 females).36
The test substance was applied to intact skin (24 h semi-occlusive application) at a dose of
2,000 mg/kg body weight. None of the animals died and there were no signs of systemic toxicity or dermal irritation.
Necropsy findings were not indicative of any abnormalities, and an LD50 of > 2,000 mg/kg body weight was reported.
Ethyl Pelargonate
According to Opdyke,29
the acute dermal LD50 in rabbits exceeded 5 g/kg.
Isononyl Alcohol
Scala and Burtis30
evaluated the acute dermal toxicity of undiluted isononyl alcohol using 4 rabbits. The test
substance was applied (under occlusive binding) to clipped, abraded abdominal skin at the following doses: 0.500,
0.200, 0.794, and 3.16 g/kg. An acute dermal LD50 of 3.2 g/kg was reported. Signs of percutaneous toxicity were not
observed. Limited results relating to the percutaneous absorption of isononyl alcohol are included earlier in the report
text. Results relating to the skin irritation potential of isononyl alcohol are included later in the report text.
Neopentyl Glycol Diisononanoate
The acute dermal toxicity of undiluted neopentyl glycol diisononanoate was evaluated using 10 Sprague-
Dawley CD strain rats (5 males, 5 females).41
A dose of 2,000 mg/kg body was applied according to the procedure in
the preceding section on Cetearyl Nonanoate. None of the animals died and there were no signs of systemic toxicity or
dermal irritation. Necropsy findings were not indicative of any abnormalities, and an LD50 of > 2,000 mg/kg was
reported.
ACUTE INTRAVENOUS TOXICITY
Oro and Wretlind 45
studied the acute intravenous (i.v.) toxicity of pelargonic acid using 10 mice (weights = 13
to 34 g). An LD50 of 224 ± 6 mg/kg was reported. Similarly, an LD50 of 224 mg/kg was reported for mice dosed i.v.
with undiluted pelargonic acid.28
ACUTE INTRAPERITONEAL TOXICITY
In a study involving rats, intraperitoneal (i.p.) dosing with undiluted pelargonic acid resulted in death, and the
lowest lethal dose (LDLo) was 3200 mg/kg.28
The dosing (i.p.) of mice with a 10% solution of pelargonic acid in corn
oil resulted in death, and an LDLo of 1600 mg/kg was reported.28
SHORT-TERM ORAL TOXICITY
Short-term oral dosing with pelargonic acid yielded an LOEL of 5,000 ppm in rats. Overt signs of toxicity
were not associated with higher doses. Limited numbers of rats given isononyl alcohol at 1 mmol/kg/day had no overt
signs of toxicity. The NOAEL for neopentyl glycol in rats was 100 mg/kg.
Pelargonic Acid
9
A study by Hazleton Labs America Inc.46
was conducted to determine the appropriate dose level of pelargonic
acid for a teratology screening study. Groups of 6 Cesarean-derived, Sprague-Dawley rats (sexually mature; weights =
177 to 285 g) were used. The test substance was administered (via oral intubation) in corn oil, at 3 dose levels (200,
1000, and 2000 mg/kg/day; 6 inseminated females/dose level) from days 6 to 15 of gestation. The dose volumes
corresponding to the administered doses (lowest to highest) were 1.0, 5.0, and 10.0 ml/kg. The control group (6
inseminated females) was dosed with corn oil according to the same procedure. All surviving rats were killed after
gestation day 15 and necropsied.
There were no remarkable clinical signs in any of the rats dosed with pelargonic acid, and none of the rats
died. Mean food consumption in the 200 mg/kg dose group was significantly higher, up to gestation day 14, when
compared to the control group. Gross pathology findings were observed principally in the lungs, kidneys, or stomach.
The numbers of rats with gross lesions included 2 rats at the 200 mg/kg dose level and one rat each at the 1000 and
2000 mg/kg levels. It was agreed that the only pelargonic acid-induced effect was on body weight. Study results
relating to reproductive and developmental toxicity are included in the Section on Reproductive and Developmental
Toxicity later in the report text.46
In another short-term study,47
the oral toxicity of pelargonic acid was evaluated using groups of 6-week-old
albino rats (Crl:CD®(SD)BR strain). Four groups (15 males and 15 females per group) were fed pelargonic acid in the
diet at concentrations of 10, 100, 1000, and 5000 ppm, respectively. Ten rats per sex in each group received their
respective diet for 28 days and until necropsy; a fifth group received basal diet only. After 28 days of pelargonic acid
(in diet) feeding, the remaining rats (5 males and 5 females per group) in the 4 groups were switched to a basal diet, and
feeding was continued for an additional 56 days (recovery phase). The fifth group was allowed to continue on the basal
diet. Necropsy was also performed at the end of the recovery phase. The results of ophthalmic examinations are
included in the section entitled Ocular Irritation/Toxicity later in the report text. Compared to the control group, male
rats in the 5000 ppm dietary group had significantly lower (p < 0.05) group mean body weights during weeks 1 through
4. The same was true for female rats in this group during weeks 3 through 6. Changes in mean body weights, body
weight gains, and food consumption in the 100 ppm and 1000 ppm dietary groups were influenced by an approximately
30-h water deprivation, which occurred during week 3. Reversible changes in clinical pathology variables (blood/urine)
following dietary administration of 5000 ppm pelargonic acid were noted.
Treatment-related morphologic changes were noted in the hearts and livers of rats killed after 28 days.
Changes in the heart were also observed in male rats during the recovery phase, but at a lower incidence and severity.
Liver lipid content was greater in female rats on diets containing 100, 1000, and 5000 ppm pelargonic acid. The lower
body weights in rats killed after 28 days resulted in greater relative weights in a number of organs. Absolute liver
weights were greater in male rats that received 5000 ppm pelargonic acid and in female rats that received 1000 ppm and
5000 ppm pelargonic acid in the diet. All other changes that were observed were considered to have been of no
toxicological importance. It was concluded that pelargonic acid appeared to have increased the risk of cardiac changes
in treated male and female rats and hepatic changes in female rats that received 5000 ppm in the diet. Changes in the
liver were not observed at 56 days post-treatment, while cardiac changes persisted at a reduced intensity.
The lowest-observable-effect-level (LOEL) for pelargonic acid was 100 ppm for antemortem data (lower body
weights) and 5000 ppm for clinical pathology in rats of both sexes. Taking into consideration the increased liver
weights observed after dosing with pelargonic acid, the LOEL was 5000 ppm for male rats and 100 ppm for female rats;
the LOEL for macroscopic effects on the liver was 1000 ppm in rats of both sexes. Regarding both cardiac and hepatic
effects, the LOEL for macroscopic changes was 1000 ppm (male rats) and 100 ppm (female rats). However, it was
noted that because histopathology was not performed on livers from lower dose rats from the scheduled sacrifice, the
LOEL for microscopic liver changes may actually be lower than these values.47
A short-term oral toxicity study was conducted using groups of 6 Sprague-Dawley albino rats (3 males, 3
females/group).48
Six groups were fed pelargonic acid in the diet at concentrations ranging from 1500 ppm to 20,000
ppm (one dietary concentration per group) for 2 full weeks. A seventh group (control) was fed untreated feed. Feeding
with pelargonic acid did not induce any adverse effects over the range of concentrations evaluated. Body weight gain
and food consumption were normal throughout the study. Other than piloerection (not dose-related), no clinical signs
10
were observed. All animals appeared healthy and normal at the time of necropsy. Hematology parameters were all
within normal limits, and the same was true for most of the serum clinical chemistry parameters.
Except for the lowest dose group, mean serum alkaline phosphatase activity was significantly greater than the
control value. Effects on alkaline phosphatase activity were not considered toxicologically significant relative to liver
function, taking into consideration the absence of an effect of pelargonic acid on serum alanine aminotransferase and
serum protein content. Total bilirubin was elevated in some of the groups, controls included; high values correlated
primarily with the presence of hemolysis in individual blood samples. It was concluded that pelargonic acid did not in-
duce overt signs of toxicity in albino rats, when fed in the diet at concentrations up to 20,000 ppm (2%) for 2 weeks. 48
In another study,28
8 male rats (weights not stated) were fed 4.17% pelargonic acid in the diet (2100 g/kg/day)
for 4 weeks. A slight decrease (4%, not statistically significant) in mean growth was observed. No effects on survival
were noted.
Isononyl Alcohol
In a study by Rhodes et al.,49
isononyl alcohol was administered by gavage to 5 male rats (Alderly Park
Wistar-derived). The test substance (in polyethylene glycol 300) was administered for 14 days at a dose level that was
equivalent to 1 mmol/kg/day. Control animals (10 rats) were dosed with polyethylene glycol 300 (10 ml/kg/day).
Livers were removed, weighed, and homogenized for enzyme assays. Testis weights were also determined. No major
pathological signs of hepatotoxicity resulted from oral dosing with isononyl alcohol. Minor histological changes
consisted of slight centrilobular hypertrophy and fat type vacuolation in control and test animals. No effects on body
weight gain or testis weight were noted. Isononyl alcohol also did not induce peroxisome proliferation,
hypocholesteremic/hypotriglyceridemic effects, or effects on catalase. However, compared to controls, isononyl
alcohol dosing resulted in slight elevation of palmitoyl CoA oxidase (marker enzyme for peroxisome proliferation).
Neopentyl Glycol
A combined repeated dose and reproductive/developmental toxicity study on neopentyl glycol was performed
using groups of male and female rats of the Slc: SD strain.43
The test substance, in distilled water, was administered by
gavage at doses of 100, 300, or 1,000 mg/kg/day. Control rats were dosed with distilled water. Male rats were dosed
over a 42-day period and female rats were dosed from 14 days before mating to day 3 of lactation. There were no dead
or abnormal animals with clinical signs related to dosing . Body weight and food consumption data were not indicative
of consistent or treatment-related differences between test and control groups. Liver and kidney weights (absolute and
relative) were increased in male and female rats of the 300 and 1,000 mg/kg dose groups. Necropsy revealed
hypertrophy of the liver in 2 males dosed with 1,000 mg/kg; definite lesions were not found at microscopic
examination. A high incidence of protein casts, hyaline droplets, and basophilic change was reported for renal tubules
in males dosed with 1,000 mg/kg. The NOAEL for this study was of 100 mg/kg. Results relating to reproductive and
developmental toxicity are included later in the report text.
SHORT-TERM DERMAL TOXICITY
Repeated applications of pelargonic acid (25% in mineral oil) to the skin of rabbits in a 28-day study did not
cause death, and the random inflammatory changes observed in various organs were described as spontaneous. In
other studies, dermal application of pelargonic acid to mice over a 3-day period did not cause death and a TDLo of
3,000 mg/kg was reported.
Pelargonic Acid
A 28-day dermal toxicity study50
was conducted using groups of New Zealand White rabbits (5 males, 5
females/group). Weight ranges were 2.1 to 3.2 kg (males) and 2.3 to 3.2 kg (females). Pelargonic acid (25% w/w
mixture in mineral oil) was applied to the skin at doses of 500 mg/kg/day (dose volume = 2 ml/kg) daily for a total of
10 applications. The test substance was applied directly to the skin and spread evenly over the test site; patches were
not applied. The skin of half of the rabbits per group (3 males, 2 females) was abraded prior to application. The control
11
group was dosed with mineral oil according to the same procedure. For necropsy, 6 rabbits per group (3 with abraded
skin and 3 with intact skin) were killed at 2 weeks and surviving animals were killed at 4 weeks.
Slight weight loss (0.1 to 0.4 kg) was noted in most of the rabbits dosed with pelargonic acid after 1 and/or 2
weeks of the study. Weight gain was noted in rabbits that were held for a 2-week recovery period. Slight to moderate
weight gains were also noted in vehicle control rabbits. None of the rabbits dosed with pelargonic acid died. Skin
reactions are summarized in the section on Skin Irritation later in the report text. Discoloration of the gastric mucosa
was observed in treated animals; other gross morphologic findings in treated and/or control animals were not
considered treatment-related. Inflammatory changes observed in the kidneys, lungs, and brain and, less frequently, in
other organs were not considered treatment-related.50
In a study by Montelius et al.,51
undiluted pelargonic acid (25 µl) was applied to both ears (dorsum) of inbred
CBA/Ca mice (groups of 4) once per day for 3 consecutive days. None of the animals died. Murine local lymph node
assay (LLNA) results are included in the section on Skin Irritation and Sensitization later in the report text.
Following intermittent dermal application of pelargonic acid to the skin of mice over a 3-day period, the 3
ml/kg dose was the lowest dose that caused a toxic effect (TDLo). In a similar study involving mice, a TDLo of 3000
mg/kg was reported.52
SUBCHRONIC ORAL TOXICITY
Ethyl Pelargonate
According to Opdyke, 29
no effects were observed at microscopic examination of the following tissues from
rats (5 males, 5 females) fed 1% ethyl pelargonate in the diet for 16 weeks: liver, kidney, heart, spleen, testes, viscera,
and hind limb. Terminal hematological examinations and gross pathology and weights of the liver, kidney, heart,
spleen, and testes did not differ from findings in control rats.
OCULAR IRRITATION/TOXICITY
The ocular changes observed in a 28-day oral toxicity study (rats) on pelargonic acid were considered
sporadic and unrelated to treatment. In studies involving rabbits, pelargonic acid (0.1 ml) was severely irritating or
mildly irritating. Neither isononyl isononanoate nor ethylhexyl pelargonate (0.1 ml) induced ocular irritation in
rabbits; however, both cetearyl nonanoate and neopentyl glycol diisononanoate (0.1 ml) induced minimal ocular
irritation and isononyl alcohol (0.1 ml) induced marked ocular irritation. PEG-5 isononanoate (0.1 ml) induced
transient ocular reactions, but was not classified as an ocular irritant.
Pelargonic Acid
Results from ophthalmic examinations were presented in the 28-day oral toxicity study on pelargonic
Acid in rats,47
summarized in the section on Short-Term Oral Toxicity earlier in the report text. Results of the interim
and terminal ophthalmic examinations were as follows: choroidal hypoplasia (1 male - 5000 ppm, 2 females - 100 ppm,
1 female - 10 ppm); retinal hemorrhage (1 female - 100 ppm); vitreous hemorrhage (1 female - 5000 ppm) - all interim
results; and hypoplasia (1 male - control); ocular discharge (1 male - 100 ppm, 1 female - control); and choroidal
hypoplasia (1 female - 100 ppm) - all terminal results. These findings were considered sporadic and unrelated to
treatment.
EPA25
placed pelargonic acid in toxicity category II (corneal involvement or other eye irritation clearing in 8-
21 days), based primarily on results from the following primary ocular irritation study involving 6 Hra: (NZW)SPF
adult albino rabbits.53
The undiluted test substance (0.1 ml) was instilled into the right eye of each animal, and
untreated left eyes served as controls. Instillation was followed by a 21-day observation period. Pelargonic acid
induced corneal and iridial involvement and severe conjunctival irritation. All reactions had cleared by day 21 post-
instillation. The average primary irritation score (5-animal mean) was 40.6 at 1 hour and 0 at day 21.
According to STN,52
pelargonic acid was a mild irritant when instilled into the rabbit eye at a dose of 0.1 ml.
12
Cetearyl Nonanoate
The ocular irritation potential of cetearyl nonanoate (97% pure) was evaluated using 3 male New Zealand
white rabbits.36
The test substance (0.1 ml) was instilled into the right eye of each animal and reactions were scored at
approximately 1 h and 24 h, 48 h, and 72 h post-instillation. Moderate conjunctival irritation was observed; however,
there were no changes in the cornea or iris. All eyes appeared normal at 48 h post-instillation. Cetearyl nonanoate was
classified as minimally irritating to the rat eye.
Isononyl Isononanoate
According to Evonik Industries,38
isononyl isononanoate was not irritating to the eyes of rabbits. Study details
were not provided.
Ethylhexyl Pelargonate
The ocular irritation potential of undiluted ethylhexyl pelargonate was evaluated using 6 New Zealand white
rabbits.39
Eyes were not rinsed following instillation of the test substance (0.1 ml). Contralateral eyes served as
controls. Reactions were scored up to 72 h post-instillation. Ethylhexyl pelargonate was not irritating to the eyes of
rabbits.
Neopentyl Glycol Diisononanoate
A study evaluating the ocular irritation potential of neopentyl glycol diisononanoate in rabbits was conducted
according to the procedure in the preceding section on Cetearyl Nonanoate. 41
Neopentyl glycol diisononanoate (0.1
ml) produced similar results and also was classified as a minimal ocular irritant.
PEG-5 Isononanoate
The ocular irritation potential of PEG-5 isononanoate was evaluated using 3 female SPF albino rabbits 42
according to the procedure in the preceding section on Cetearyl Nonanoate. Conjunctival redness and edema had
cleared within 14 days, and PEG-5 isononanoate was classified as a non-irritant.
Isononyl Alcohol
In a study by Scala and Burtis,30
undiluted isononyl alcohol was instilled (0.1 ml) into the left conjunctival sac
of each of 6 rabbits. Untreated eyes served as controls. Ocular irritation reactions were scored using the Draize scale (0
to 110). Draize median irritation scores of 30 (at 24 h) and 2 (at day 7) were reported. The ocular irritation induced by
isononyl alcohol was classified as marked. The test substance did not produce severe opacity or other corneal effects,
such as sloughing or vascularization.
SKIN IRRITATION
Undiluted pelargonic acid was a mild to severe skin irritant in rabbits and a severe skin irritant in guinea
pigs, but was not irritating to the skin of mice. The remaining studies involved rabbits only. Isononyl isononanoate and
undiluted PEG-5 isononanoate were slightly/mildly irritating and undiluted ethyl pelargonate was moderately irritating
to the skin; however, undiluted isononyl alcohol induced marked skin irritation. Skin irritation was not observed
following the application of undiluted cetearyl nonanoate, cetearyl isononanoate, or undiluted ethylhexyl pelargonate.
Pelargonic Acid
According to Opdyke,29
pelargonic acid was classified as a strong skin irritant in guinea pigs, and a moderate
irritant when applied undiluted (under occlusion) to abraded or intact skin of rabbits for 24 h.
In a 28-day dermal toxicity study (in Short-term Dermal Toxicity section earlier in report text),50
slight to
severe erythema and edema without necrosis or eschar formation were observed in most of the rabbits during the first
week of the study. Generally, during the second week, necrosis and eschar formation were observed in all rabbits.
Atonia, desquamation, fissuring, and exfoliation were also observed. In rabbits held for recovery, dermal responses
13
subsided. At microscopic examination, epidermal necrosis, hyperplasia, and hyperkeratosis were noted at the
application site. Diffuse and perifollicular dermal inflammation were also common. The skin application sites in all
surviving animals appeared healed by 2 weeks post-treatment (scheduled recovery period).
EPA25
placed pelargonic acid in toxicity category II (severe irritation at 72 h [severe erythema or edema]),
based primarily on results from the following skin irritation study involving 6 adult female albino rabbits of the Hra:
(NZW) SPF strain.54
The test substance (undiluted) was applied to intact skin of the back (0.5 ml, exposure area ≈ 6.25
cm2), and the site was covered with a semi-occlusive patch for 4 hours. Reactions were scored up to day 21 post-
removal. Skin irritation was observed in all animals; reactions ranged from moderate to severe erythema and edema.
The average of the 4-, 24-, 48-, and 72-hour scores was 5.6 (severely irritating). The following observations were also
made at application sites: subcutaneous hemorrhaging, blanching, desquamation, fissuring, possible necrotic areas,
denuded areas, and possible scar tissue. With the exception of a denuded area in one animal, all irritation reactions had
cleared by day 21.
In a study by Montelius et al.,51
undiluted pelargonic acid (25 µl) was applied to both ears (dorsum) of inbred
CBA/Ca mice (groups of 4) once per day for 3 consecutive days. Skin irritation (erythema, edema) was not observed at
the test sites. LLNA results are included in the section on Skin Irritation and Sensitization later in the report text.
According to STN,52
pelargonic acid (500 mg dose) was moderately irritating, following application to rabbit
skin for 24 h. Undiluted pelargonic acid was classified as a severe irritant, following application to guinea pig skin.
Cetearyl Nonanoate
The skin irritation potential of cetearyl nonanoate (97% pure) was evaluated using 3 male New Zealand white
rabbits.36
The test substance (0.5 ml) was applied to skin clipped free of hair and the application site was covered with a
semi-occlusive patch for 4 h. Reactions were scored 1 h after patch removal and 24 h, 48 h, and 72 h later. Cetearyl
nonanoate was classified as a non-irritant.
Cetearyl Isononanoate
According to Evonik Industries,37
Cetearyl Isononanoate was not irritating to the skin of rabbits. Study details
were not provided.
Isononyl Isononanoate
According to Evonik Industries,38
Isononyl Isononanoate was slightly irritating to the skin of rabbits tested
according to OECD method 404. Additional study details were not provided.
PEG-5 Isononanoate
The skin irritation potential of undiluted PEG-5 Isononanoate was evaluated using 3 male New Zealand white
rabbits.42
The test substance (0.5 ml) was applied to skin clipped free of hair and the application site was covered with a
semi-occlusive patch for 4 h. Reactions were scored 1 h after patch removal and 24 h, 48 h, and 72 h later. The test
substance induced well-defined erythema and very slight edema; no corrosive effects were observed. PEG-5
isononanoate was classified as a mild irritant (PII = 2).
Ethyl Pelargonate
According to Opdyke,29
moderate skin irritation was observed after undiluted ethyl pelargonate was applied,
under occlusion, to intact or abraded skin of rabbits for 24 h.
Ethylhexyl Pelargonate
The skin irritation potential of undiluted ethylhexyl pelargonate was evaluated using 6 New Zealand white
rabbits.39
The test substance (0.5 ml) was applied to intact and abraded skin sites that remained occluded for 24 h.
Reactions were scored at 24 h and 72 h post-application. Ethylhexyl pelargonate did not induce skin irritation in any of
the rabbits (primary irritation index [PII]= 0.40).
14
Isononyl Alcohol
The results of an acute dermal toxicity study30
on undiluted isononyl alcohol (4 rabbits, abraded skin) are
summarized earlier in the report text. The test substance was applied under an occlusive binding for 24 h, and the
doses administered ranged from 0.500 to 3.16 g/kg. In this study, dermal irritation (erythema and edema) was classified
as marked overall. Both the intensity and duration of skin irritation were dose-related. Atonia and desquamation, with
some necrosis or eschar, were persistent findings. It was noted that some of the irritation observed was associated with
the trapping of liquid under the occlusive binder at a point where the binder was bound to the animal. It was noted that
these areas of intimate contact and pressure gave rise to some of the reported necrosis and eschar.
INFLAMMATION
Ahlfors and Larsson55
conducted a study to examine the tissue response of pelargonic acid in the buccal
mucosa of the rat. Both pelargonic acid in methyl ester and pelargonic acid in propyl ester (both in acetone) were tested
using groups of 6 Sprague-Dawley rats (3 months old). The protocol used consisted of sensitization (dorsal skin) with
2% pelargonic acid (both solutions; dose volume = 100 µl) and challenge in the buccal mucosa (dose volume = 50 µl)
with different concentrations of the sensitizing solution (0.2% and 2.0%). The area of the application site (cm2) was not
stated. Allergenic potential, as evidenced by the tissue response in the buccal mucosa, was investigated using a skin
sensitization procedure and elicitation with 2% or 0.2% solutions. Control rats were exposed to acetone only. The
animals were killed 48 h after the last application, and the right buccal mucosa was excised and prepared for
microscopic examination. Cellular infiltrates in the buccal mucosa were recorded and compared to normal rat buccal
mucosal.
Both test substances (at both concentrations) caused increased cellularity, mainly of the mononuclear cell type.
The low concentration of pelargonic acid in methyl ester induced stronger inflammatory reactions than the high dose.
This finding was the opposite of that reported for pelargonic acid in propyl ester. Both substances were said to have
shown a sensitization tendency. Repeated applications of 2% pelargonic acid in propyl ester decreased the
inflammatory response, when compared to one application. However, for pelargonic acid in methyl ester, a clear
irritative potential was noted with repeated applications. Pre-exposure of dorsal skin prior to buccal painting resulted in
an enhanced reaction to pelargonic acid in methyl ester and pelargonic acid in propyl ester.55
SKIN IRRITATION AND SENSITIZATION
In a guinea pig RIPT, pelargonic acid (50% in corn oil) was irritating during induction, but was not a
sensitizer. In guinea pig maximization tests, cetearyl nonanoate (10% in sesame oil) and undiluted neopentyl glycol
diisononanoate were non-sensitizers; results for 50% cetearyl nonanoate in sesame oil and undiluted neopentyl glycol
diisononanoate (for induction) were negative in preliminary skin irritation tests. In mouse LLNAs (for sensitization
potential), results were positive at pelargonic acid concentrations of ≥ 50% and ≥ 20% (no-effect-level = 10%) and
negative for PEG-5 isononanoate at concentrations up to 100%.
Pelargonic Acid
The skin sensitization potential of pelargonic acid was evaluated in a repeated insult patch test using 24 male
albino guinea pigs.56
The test group consisted of 10 animals and negative (corn oil) and positive (2,4-
dinitrochlorobenzene - DNCB) control groups contained 10 and 4 animals, respectively. During induction, pelargonic
acid (50% w/v mixture in corn oil, 0.5 ml) was placed on an adhesive patch (Hill Top Chamber®, 25-mm diameter) that
was applied to shaved skin of the anterior left flank for 6 hours per application. Following a non-treatment period, a 6-
hour challenge application of the test mixture (0.4 ml) was made to the anterior right flank of each test animal and corn
oil was also applied to a new site on the anterior left flank. The 10 negative control animals were not treated during
induction, but received challenge applications of the test mixture and corn oil alone. The positive control was applied
during induction and challenge phases.
15
Pelargonic Acid (50% w/v mixture in corn oil) induced moderate to strong dermal reactions (erythema/edema)
in all 10 guinea pigs during the induction phase. Dermal reactions to the mixture were not observed in negative control
animals during the challenge phase. The test mixture also did not elicit any dermal reactions in test animals during the
challenge phase, and was considered a non-sensitizer in guinea pigs. The positive control induced sensitization.56
In a study by Sikorski et al.,57
3 female BALB/c mice or female CBA/J mice (Harlan) (6 weeks old; weights ≈
17 to 23 g) were treated with pelargonic acid for 3 consecutive days. The test substance was applied topically (25 µl
total/ear; application area [cm2] not stated) to both ears at concentrations ranging from 20% to 80% pelargonic acid in
1-propanol (v/v) and an LLNA was performed according to the procedure of Kimber and Basketter.58
The LLNA
measures the proliferative response of lymphocytes in the draining lymph nodes during the induction of contact
sensitization by epicutaneous exposure to an allergen.
Compared to the vehicle control, pelargonic acid produced slight increases in the % of B220+ lymphocytes at
all doses. These findings were not dose-related. Even at high concentrations, the cell number per node and the % of
B220+ cells never approached the values that were associated with allergens such as 1-chloro-2,4,6-trinitrobenzene
(TNCB) and 1-chloro-2,4-dinitrobenzene (DNCB).57
In an effort to develop a predictive in vitro assay for the identification of potential contact allergens, Pistoor et
al.59
compared the effects of epicutaneous application of known contact allergens, pelargonic acid and other known
irritants, and dermatologically inactive chemicals on Langerhans cells in skin biopsy cultures from 7 healthy donors.
The skin specimens were obtained from breast reduction surgery or abdomen reduction surgery. Pelargonic acid (80%
v/v) in propane-1-ol and 100% propylene glycol was tested. Untreated and treated skin samples were cultured for 24 h.
As controls, explants were topically treated with the solvent.
Immunohistochemical analysis of cryostat sections of all biopsies treated with contact allergens showed the
following: (1) a large decrease in the number of Langerhans cells in the epidermis, as evaluated by a decrease in human
leukocyte antigen (HLA)-DR+- expressing cells and CD1a
+- expressing cells. (2) accumulation of the remaining
Langerhans cells at the epidermal-dermal junction. Pelargonic acid did not induce these changes.59
Montelius et al.51
evaluated pelargonic acid, neat or in dimethylformamide, in the LLNA. Pelargonic acid
showed a dose-response relationship and, clearly, positive results when tested at concentrations of ≥50%. Thus, this
chemical was classified as a potential sensitizer. Short-term oral toxicity results for inbred CBA/Ca strain mice used in
this assay are summarized under that subheading earlier in the report text. Similarly, results relating to skin irritation
are summarized in the Skin Irritation section.
Woolhiser et al.60
combined the parameters of an LLNA and a mouse ear swelling irritancy assay in an effort
to establish a single, rapid screening procedure for the sensitization and irritation potential of chemicals. Groups of 5
female B6C3F1 mice (C57BL/6 x C3HHeN; weights = 18 to 26 g) were used. Pelargonic acid was administered to the
dorsal and ventral surfaces of each ear at concentrations ranging from 5% to 60% (in acetone) for 4 consecutive days.
Compared to the vehicle control, pelargonic acid produced a dose-dependent and statistically significant increase in
lymph node cell proliferation at concentrations of 20%, 40%, and 60%. The no-effect-level was at a concentration of
10%. Known sensitizers (i.e., oxazolone; 2,4-dinitrofluorobenzene; and toluene diisocyanate) evaluated in the assay
produced marked lymph node cell proliferation.
Cetearyl Nonanoate
The skin sensitization potential of cetearyl nonanoate (89% pure) in sesame oil was evaluated in a
maximization test using 15 male guinea pigs.36
Of the 15, 5 comprised the vehicle control group. Because topical
induction with 50% cetearyl nonanoate in sesame oil did not induce skin irritation in a preliminary experiment, the skin
was treated with sodium lauryl sulfate (SLS) in order to induce local irritation. Cetearyl nonanoate (10% in sesame oil)
was administered during the first (intracutaneous) induction stage, and reactions were evaluated after 24 and 48 h.
During the second (topical) induction stage, cetearyl nonanoate (50% in sesame oil, 2 ml) was applied and reactions
were scored 48 and 72 h after the initiation of exposure. At day 21, the animals were challenged with 10% cetearyl
nonanoate in sesame oil (2 ml). Skin changes were not observed following intracutaneous induction or during the
challenge phase, and the same was true for the vehicle control. Cetearyl nonanoate was classified as a non-sensitizer.
16
Neopentyl Glycol Diisononanoate
A maximization test on neopentyl glycol diisononanoate was performed according to a slight modification of
the preceding test procedure.41
Undiluted test material was applied during the second induction and challenge phase.
Initially, the skin was treated with SLS because topical induction with undiluted neopentyl glycol diisononanoate did
not induce skin irritation in a preliminary experiment. Neopentyl glycol diisononanoate was classified as a non-
sensitizer.
PEG-5 Isononanoate
The skin sensitization potential of PEG-5 isononanoate in CBA/Ca mice (groups of 4) following topical
application was evaluated in the local lymph node assay.42
The undiluted test substance and concentrations of 25% and
50% in acetone/olive oil were applied to the dorsal surface of the ear. The control group was treated with vehicle only.
The stimulation index (SI) was expressed as the mean radioactive incorporation for each treatment group divided by the
mean radioactive incorporation of the vehicle control group. SI values of 1.70 (25% concentration), 2.42 (50%), and
1.85 (100%) were reported, and PEG-5 isononanoate was classified as a non-sensitizer.
REPRODUCTIVE AND DEVELOPMENTAL TOXICITY
Daily doses of pelargonic acid up to 1,500 mg/kg/day did not induce reproductive effects in inseminated
female rats. Results from other studies support pelargonic acid daily doses of 1500 mg/kg/day as the no-observable-
effect-level for maternal/developmental toxicity in rats. Two branched-chain nonanols (perhaps incorrectly identified
as isononanol) caused a marked degree of maternal and fetal toxicity in rats at daily doses of 7.5 and 10 mmol/kg/day
(1,185 and 1,580 mg/kg/day) and slight fetal effects at 5 mmol/kg/day doses. Neopentyl glycol at oral doses up to 1,000
mg/kg/day did not induce reproductive effects.
Pelargonic Acid
A study by Hazleton Labs America Inc.28
conducted to determine the appropriate dose level of pelargonic acid
for a teratology screening study involving Cesarean-derived, Sprague-Dawley rats. Details relating to the conduct of
this study are included in the section on Short-Term Oral Toxicity earlier in the report text. The number of corpora
lutea per ovary and the number and placement of uterine implantations, resorptions, and live and dead fetuses were
recorded. Mean ovarian and uterine weight data were comparable between treated and control groups. No treatment-
related reproductive effects were noted over the range of administered doses (1.0 to 10.0 ml/kg).
A study designed to evaluate the embryo/fetal toxicity and teratogenic potential of pelargonic acid was
conducted using groups of 22 mated female Crl:COBS, CD®(SD)BR rats (14 weeks old).61
Females of the test group
were dosed orally (by gavage) with pelargonic acid (in corn oil; dose = 1500 mg/kg) on gestation days 6 through 15.
The control group received corn oil according to the same procedure. Pregnant females were killed on day 20 and
fetuses were delivered by cesarean section. Neither test substance-related maternal toxicity nor effects on food and
water consumption were observed in the test or control group. Additionally, there was no definitive evidence of
teratogenic effects in the test or control group.
EPA25
reported the results of a developmental toxicity study involving rats. Treatment of the animals with
pelargonic acid had no adverse effects on clinical signs, body weight gain, or food/water consumption. Fetal toxicity
was not observed in treated rats or in untreated control rats, and the following parameters were comparable between
treated and control rats: mean number of viable fetuses, early or late resorptions, implantation sites, corpora lutea, pre-
and post-implantation losses, sex ratios, and fetal body weights. The no-observed-effect level (NOEL) for maternal and
developmental toxicity was 1500 mg/kg/day, and the LOEL was greater than 1500 mg/kg/day.
17
Isononyl Alcohol
Hellwig and Jäckh62
studied the developmental toxicity of isononyl alcohol using sexually mature, virgin
Wistar rats of outbred strain Chbb/THOM. The 2 types of isononyl alcohol, both identified as CAS No. 68515-81-1,
tested were defined as follows: Isononanol type 1 (purity ≥ 99%) – of commercial origin and consisted of roughly
equivalent amounts of 3,4-, 4,6-, 3,6-, 3,5-, 4,5-, 5,6-dimethylheptanol-1. Isononanol type 2 (purity ≥ 99%) – produced
at BASF and the following were listed as main components: 4,5-diemthylheptanol-1 (~23%), 4-methyloctanol-1
(29%), 3-ethylheptanol-1 (3%), 6-methyloctanol-1 (15%), and 3-ethyl-4-methylhexanol (1%) [Note: Based on these
chemical composition data, there is reason to believe that neither chemical (type 1 or 2) is isononanol. However, it is
evident that both are branched-chain nonanols]. The test substances were diluted (twice-distilled water, employing ~
0.005% Cremophor EL [PEG-35 Castor Oil] as emulsifier) to a standard dose volume of 5 ml/kg body weight. Each
test substance was administered by gavage (doses ranging from 1 to 10 mmol/kg/day) to pregnant females (10/group)
on days 6 to 15 post-coitum. Two control groups were treated with either doubly-distilled water alone (control group 1)
or water plus ~ 0.005% Cremophor EL (control group 2).
Both isononanols (types 1 and 2) exhibited a marked degree of maternal and fetal toxicity at daily doses of 7.5
and 10 mmol/kg/day, and slight fetal effects at 5 mmol/kg/day doses. Of the fetal findings (malformations, variations,
or retardations), the only ones that were significantly different from controls were the number of fetuses with skeletal
retardations in the 5 mmol/kg/day dose group (p < 0.1, both control groups) and the number with skeletal variations in
this group (p < 0.05; 1 control group). Dosing at 1 mmol/kg/day did not cause adverse effects. When pregnant females
were dosed with 7.5 mmol/kg /day (isononanol type 1) in a supplementary experiment, the incidence of malformations
(mainly related to the heart) was statistically significantly increased (p < 0.01; 1 control group). Resorptions and post-
implantation loss were also significantly increased (p < 0.01; 1 control group) at this dose level. For isononanol type 2,
the only significant fetal findings (7.5 mmol/kg/day doses) were the number of fetuses with skeletal retardations (p <
0.01, 0.05; 1 control group – both values), number of fetuses with skeletal variations (p < 0.051 1 control group),
number of fetuses with variations (p < 0.05; 1 control group) and number of fetuses with malformations (p < 0.05; 1
control group). Resorptions were also significantly increased (p < 0.05; both control groups).
Neopentyl Glycol
A combined repeated dose and reproductive/developmental toxicity study on neopentyl glycol was performed
using groups of male and female rats of the Slc: SD strain.43
The test substance, in distilled water, was administered by
gavage at doses of 100, 300, or 1,000 mg/kg/day. Control rats were dosed with distilled water. Male rats were dosed
over a 42-day period and female rats were dosed from 14 days before mating to day 3 of lactation.
There were no test substance-related effects on copulation, fertility, or the estrous cycle of rats, and the same was true
during the lactation period. With the exception of one control rat, delivery was normal for all dams. There were no test
substance-related abnormal findings in any of the pups delivered. The body weight gain of pups was normal up to day
4 of lactation. Test substance-related, abnormal gross findings were not reported for stillborn, dead pups or pups killed
at day 4 of lactation. Additionally, no developmental toxic effects were associated with test substance administration.
The NOAEL for neopentyl glycol (P and F1 generations) was 1,000 mg/kg. Results relating to the short-term oral
toxicity of neopentyl glycol are included earlier in the report text.
GENOTOXICITY
While one mammalian cell assay of pelargonic acid was positive with metabolic activation, it was negative
without metabolic activation and all other bacterial, mammalian cell, and in vivo assays for pelargonic acid and the
following pelargonic acid esters were negative: cetearyl nonanoate, ethylhexyl isononanoate, neopentyl glycol
diisononanoate, and PEG-5 isononanoate.
Pelargonic Acid
In an Ames test,63
the mutagenicity of pelargonic acid was evaluated with and without metabolic activation
using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538. The test substance (in dimethyl
sulfoxide [DMSO]) was evaluated at doses ranging from 100 to 5,000 µg/plate in this reverse mutation assay.
18
Pelargonic acid did not cause a positive increase in the number of histidine revertants per plate in any of the tester
strains, with or without metabolic activation, and, therefore, was nonmutagenic.
The mutagenicity of pelargonic acid was evaluated in a forward mutation assay, using the L5178Y mouse
lymphoma cell line.64
In preliminary cytotoxicity assays, pelargonic acid (in DMSO) induced dose-related cytotoxicity,
and was completely toxic at a dose of 4,000 µg/ml (without metabolic activation) and at a dose of 2,000 µg/ml (with
metabolic activation). In forward mutation assays without metabolic activation (doses of 150 to 1600 µg/ml),
pelargonic acid did not induce repeatable increases in the mutant frequency. In assays with metabolic activation, dose-
related increases in the mutation frequency that exceeded the minimum criterion for a positive response were observed
at doses ranging from 150 to 600 µg/ml. These increases were primarily due to increases in small colonies, considered
to reflect gross chromosomal changes rather than small changes within a gene. Results for pelargonic acid were
positive with metabolic activation, but negative without metabolic activation.
The mutagenicity of pelargonic acid was evaluated in the in vivo micronucleus assay.65
Three groups of ICR
mice (5 males, 5 females/group) received pelargonic acid, in corn oil, at oral doses of 1250, 2500, and 5000 mg/kg,
respectively. After dosing, the animals were killed and bone marrow was extracted. Pelargonic acid did not induce a
significant increase in micronuclei in bone marrow polychromatic erythrocytes, and was considered non-mutagenic in
this assay.
The National Toxicology Program66
evaluated the mutagenicity of pelargonic acid (in dimethylsulfoxide) in
Salmonella typhimurium strains TA 98 and TA 100 using the Ames preincubation assay. Pelargonic acid was tested at
doses up to 5000 µg/plate with and without metabolic activation, and results were negative in each strain.
Cetearyl Nonanoate
The mutagenicity of cetearyl nonanoate (in acetone; doses up to 5,000 µg/plate) was evaluated in the Ames
test using Salmonella typhimurium strains TA1535, TA1537, TA102, TA98, and TA100.36
Results were negative with
and without metabolic activation.
Ethylhexyl Isononanoate
The mutagencity of ethylhexyl isononanoate (in acetone; doses up to 5,000 µg/plate) was evaluated in the
Ames test using the bacterial strains stated immediately above.67
Results were negative with and without metabolic
activation.
Neopentyl Glycol Diisononanoate
The Ames test was also used to evaluate the mutagenicity of neopentyl glycol diisononanoate (in acetone;
doses up to 5,000 µg/plate) in the Salmonella typhimurium strains mentioned in the preceding study.41
Results were
negative with and without metabolic activation.
PEG-5 Isononanoate
A battery of mutagenicity tests on PEG-5 isononanoate was performed.42
Ames test results (doses up to 5,000
µg/plate ± metabolic activation) were negative in the Salmonella typhimurium strains mentioned in the preceding
section on Cetearyl Nonanoate. The mutagenicity of a formulation containing water, trideceth-9, and 29% PEG-5
isononanoate was evaluated in a chromosomal aberration assay involving human lymphocytes in vitro. The highest test
concentration of the formulation was 5,000 µg formulation /ml (1450 µl PEG -5 isononanoate /ml). Dose-dependent
increases in chromosomal aberrations, with metabolic activation, were within the range of the laboratory’s historical
control data, and, thus, considered biologically irrelevant. Clastogenicity was not observed, either with or without
metabolic activation. The mutagenicity of the same formulation and maximum test concentration was evaluated in the
mammalian cell gene mutation test (mouse lymphoma assay) using the L5178Y/TK+/-
cell line with and without
metabolic activation. Results were negative with and without metabolic activation.
19
Neopentyl Glycol
The mutagenicity of neopentyl glycol was evaluated using Salmonella typhimurium strains TA100, TA 1535,
TA98, and TA1537 and Escherichia coli strain WP2 uvrA.43
Mutagenicity was evaluated at doses up to 5,000 µg/plate
with and without metabolic activation. The minimum dose at which toxicity to bacteria was observed, with and without
metabolic activation, was > 5,000 µg/plate. Results for neopentyl glycol were classified as negative in this assay. The
mutagenicity of neopentyl glycol was also evaluated in an assay involving Chinese hamster CHL cells. Test substance
(in distilled water) doses up to 1.0 mg/ml were evaluated, and results were classified as negative.
Kusakabe et al.68
provided Ames test results and the results of a chromosomal aberration test, using Chinese
hamster lung (CHL/IU) cells, on neopentyl glycol. In the latter assay, proliferating cells were treated with neopentyl
glycol for 6h (short-term) with and without metabolic activation. These cells were also treated with neopentyl glycol
for 24 h and 48 h continuously without metabolic activation. Ames test results were negative. In the chromosomal
aberrations test, results for neopentyl glycol were negative at doses manifesting 50% or < 50% cytotoxicity (or at 5
mg/ml or 10 mM). Negative chromosomal aberrations test results (with and without metabolic activation) were
associated with short-term as well as continuous treatment assays.
Methyl Pelargonate
Renner69
evaluated the anticlastogenic potential of methyl esters of fatty acids in the chromosomal aberration
assay using Chinese hamster bone marrow cells. The chromosome-breaking activity of the alkylating agent bisulfan
(1,4- butandiolbis (methane sulphonate) was not modulated by the methyl ester of pelargonic acid (C9) and other short-
chain fatty acids. However, the methyl esters of fatty acids ranging from lauric acid (C12) up to nonadecanoic acid (C19)
reduced the rate of aberrant metaphases from 9.4 % to ∼3% at doses of 100 mg/kg and less.
CARCINOGENICITY
The dermal carcinogenicity of undiluted pelargonic acid was evaluated using groups of 50 male C3H/HeJ
mice.70
Pelargonic acid (dose = 50 mg/kg; was applied twice weekly to interscapular skin (clipped free of hair) of the
back for 80 weeks or until a neoplasm was grossly diagnosed as an advanced tumor. All surviving mice were killed
between 80 and 83 weeks. Other groups included in the study were an untreated control group, a group treated with
mineral oil, and a positive control group (0.05% benzo(a)pyrene in mineral oil). Sixty-six percent of the mice in the
Pelargonic Acid-treated group survived to week 78, compared to 52% and 64% for untreated and mineral oil controls,
respectively. None of the positive control mice receiving applications of 0.05% benzo(a)pyrene survived to week 78.
Forty-two mice treated with pelargonic acid lived long enough to have sufficient exposure to develop a tumor within
the average latent period.
The following non-neoplastic skin lesions were observed in pelargonic acid-treated mice: ulcer (7 mice), skin
pigmentation (41 mice), fibrosis (48 mice), scar formation (14 mice), acanthosis (48 mice), and hyperkeratosis (40
mice). The authors noted that hyperplasia of the dermis (fibrosis), acanthosis, and hyperkeratosis are common findings
in areas of mouse skin that have been clipped free of hair. There was no evidence of gross skin tumors in pelargonic
acid-treated mice or in the 2 control groups. Gross skin tumors were reported for 46 positive control mice. The
incidence of hepatocarcinomas in the test group was at least as high as that in the negative control groups after 80
weeks.70
ANTITUMOR ACTIVITY
Pelargonic Acid
Nishikawa et al.71
studied the antitumor activity of pelargonic acid using groups of 6 female ddY mice
(weights = 23 ± 2 g) inoculated i.p. with Ehrlich ascites carcinoma. Pelargonic acid (in saline with 0.2% Tween 80)
was injected i.p. once daily for 5 consecutive days. Six control mice were injected with the vehicle according to the
same procedure. None of the animals died. Pelargonic acid did not induce antitumor activity.
20
Ethyl Pelargonate
According to Opdyke,29
ethyl pelargonate (1.0 mmol/ml) induced antileukemic activity when an in vitro
mixture with AKR leukemic cells was injected subcutaneously (s.c.) into male AKR mice.
CLINICAL ASSESSMENT OF SAFETY
SKIN IRRITATION
Pelargonic acid is a known skin irritant, based on the results of both predictive and provocative human skin
irritation studies. In predictive tests, pelargonic induced skin irritation at concentrations ranging from 5% to 80%;
ethyl pelargonate was a skin irritant at a concentration of 20%, but not 12%. Predictive skin irritation test results for
undiluted cetearyl nonanoate and undiluted neopentyl glycol diisononanoate were negative.
Predictive Tests
Pelargonic Acid
Stillman al.72
conducted a cumulative irritation study involving 20 male subjects, where the relative irritancy
of free fatty acids of different chain lengths was evaluated. Equimolar concentrations (0.5 M and 1.0 M) of even- and
odd-numbered - straight chain saturated fatty acids were dissolved in propanol. Each Al-test® patch containing a fatty
acid (0.5 M) was applied to the interscapular area of 10 subjects, and, similarly, each fatty acid was applied at a higher
concentration (1.0 M) to the remaining 10 subjects. A control patch containing propanol was also applied to each
subject. Patches remained in place for 24 h and reactions were scored 30 minutes after patch removal. This procedure
was repeated daily for a total of 10 applications. In another test, each fatty acid (0.01 M and 0.1 M, in olive oil;
injection volume = 0.1 ml ) was injected into the backs of 5 additional subjects. Olive oil (control) was injected
intradermally into each subject. Test sites were evaluated for erythema and induration at 24h and 48 h.
In most men in the dermal study, an erythematous response to the 0.5 M fatty acid concentration was observed
by day 10 for fatty acids in the C8 through C12 range. Seven of 10 subjects had an erythematous reaction to pelargonic
acid (0.5 M). For the 1.0 M fatty acid concentration, an erythematous response was observed in all 10 subjects by the
eighth day of application of fatty acids in the C8 through C12 range. In both groups of 10 subjects, there were no
reactions to propanol. Following intradermal injection, slight induration (5 mm) and mild erythema were observed at
all injection sites in each of the 5 subjects (0.01 M fatty acids, 0.1 M fatty acids, and olive oil control). It was not
possible to differentiate the control sites from the test sites.72
In a study by Wahlberg and Maibach,73
116 healthy male subjects (21 to 55 years old) were patch tested with
pelargonic acid at concentrations of 5%, 10%, 20%, and 39.9% in propanol and a propanol-treated control patch was
used. Dose response curves were developed. Patches (Al-test® discs) were saturated with 0.04 ml of a test solution
and applied to the upper back for 48 h. Reactions were scored at 48 h and 96 h post-application. Pelargonic acid at
concentrations of 20% and 39.9% in propanol caused skin irritation in > 90% of the subjects tested at both 48 h and 96
h post-application. The lesions consisted primarily of erythema at 48 h and pigmentation at 96 h. Pelargonic acid (10
% in propanol) caused skin irritation in 54.3% of the subjects at 48 h post-application and in 48.5% of the subjects at 96
h. Pelargonic acid (5% in propanol) caused skin irritation in 12.9% of the subjects at 48 h post-application and in
13.9% of the subjects at 96 h post-application.
In a study by Agner and Serup,74
16 volunteers (10 females, 6 males; median age of 29.5 years) were patch
tested (closed patches, Finn chambers) with 20% pelargonic acid in propanol (pH of 4.3). Propanol was one of the
controls used. Patches were applied to the anterolateral surface of both upper arms for 24 h. Reactions were scored at
24, 48, and 96 h post-application according to the following scale: 0 (no reaction) to 3 (strong positive reaction: marked
erythema, infiltration, possibly vesicles, bullae, pustules and/or pronounced crusting). Pelargonic acid caused erythema
and slight infiltration at 24 h post-application and, occasionally, slight crusting was observed at 48 h. Scores ranging
from 0 to 3 were reported at 24 h, and scores ranging from 0 to 2 were reported at 48 h and 96 h.
21
Willis et al.75
conducted a skin irritation study using 42 healthy, non-atopic male volunteers (mean age = 34
years; skin types: II [20 subjects], III [17 subjects], and IV [5 subjects]). Pelargonic acid was patch-tested (Finn
chambers, volar forearm) at the following concentrations (in propan-1-ol): 40% (12 subjects), 60% (32 subjects), 70%
(32 subjects), and 80% (28 subjects). Each subject received between 3 and 10 patch tests. The patches remained in
place for 48 h, and reactions were scored 1 h later according to the following scale: - (no visible reaction) to 4+
(intense erythema with bullous formation). Propanol was one of the controls used. The following positive reactions
were reported: 2 of 12 subjects (40% pelargonic acid; faint, patchy erythema [+/-]), 20 of 32 subjects (60% pelargonic
acid; mostly erythema with edema [1+]), 22 of 32 subjects (70% pelargonic acid; mostly erythema with edema [1+]),
and 28 of 28 subjects (80% pelargonic acid; mostly erythema with edema [1+] and erythema with edema and papules
[2+]).
Agner and Serup76
patch tested 16 healthy subjects (ages not stated) with pelargonic acid (20% in propanol).
Closed patches (Finn chambers) containing the test substance were applied to the anterolateral surface of both upper
arms. The patches were removed at 24 h post-application and reactions were scored at 24 h and 96 h post-application.
Propanol (solvent) was also evaluated in this study. A mean irritation score of 2 (moderate positive reaction) was
reported at 24 h and a mean score of 1 (weak positive reaction) was reported at 96 h.
In a study by Willis et al.,77
10 healthy, nonatopic male volunteers (mean age = 35) were patch tested (Finn
chambers) with 80% (w/v) pelargonic acid in propan-1-ol (w/w) 100% propylene glycol and the vehicle control. The
test substance was applied to the volar aspect of the forearm for 48 h, and reactions were scored at 1 h post-removal
according to the following scale: negative to severe (erythema, edema, and vesiculation). Punch biopsy specimens were
obtained from the application site and an untreated site and examined microscopically. Patch test results for the
vehicle control were negative. Pelargonic acid induced mild to moderate skin irritation. At microscopic examination,
the most notable feature in all skin samples was the presence of “tongues” of dense, irregularly shaped eosinophilic
keratinocytes containing shrunken nuclei that extended down from the stratum granulosum and into the stratum
spinosum. The cytoplasm of these cells was composed largely of dense, wavy aggregates of osmiophilic keratin
filaments that were associated with prominent intercellular desmosomes.
Agner and Serup78
investigated pathophysiological components of irritant contact dermatitis induced by 20%
pelargonic acid in propanol using 20 healthy volunteers (12 males, 8 females; mean age = 27.5 years). A closed patch
(Finn chamber) containing the test material was applied to the flexor side of both upper arms for 24 h. Reactions were
scored at 24 h (30 to 60 min after patch removal), 48 h, and 96 h post-application. At 24 h, skin irritation (scores not
included) was observed in all 20 subjects. At 48 h, severe reactions to pelargonic acid were not observed. A significant
increase in transepidermal water loss (p < 0.01) was observed after 24 h, 48 h, and 96 h, when compared to propanol
(control) patch test areas. However, the increase was not significant after 24 h when compared to empty chamber areas.
Blood flow was significantly increased (p < 0.01) in areas patch-tested with pelargonic acid after 24 h, 48 h, and 96 h
post-application, when compared to propanol and empty chamber controls. Skin thickness was also significantly
increased (p < 0.01) throughout the observation period when compared to controls.
In another study, Agner and Serup79
investigated a possible seasonal variation in the skin response to
pelargonic acid during the winter and summer. The study was conducted using 17 healthy volunteers (10 males, 7
females; mean age = 27 years). The test substance (20% pelargonic acid in propanol) was applied (closed patch, Finn
chamber) to each arm for 24 h. Reactions were scored at 30 min post-removal. Two subjects had reactions that ranged
from a score of 0.5 to 2 during the winter and 1 subject had reactions that ranged from 1 to 2 during the summer.
Reactions were not observed at sites treated with propanol, water, or to which an empty chamber was applied. For
sites tested with pelargonic acid and control patch sites, the hydration state of the superficial epidermis was
significantly lower (p < 0.01) during the winter period, compared to the summer period. No significant seasonal
variation was found in the skin response (irritation or transepidermal water loss) to pelargonic acid.
Willis et al.80
patch tested 10 healthy, non-atopic male volunteers with 80% (v/v) pelargonic acid (in propan-1-
ol, 100% propylene glycol). Ages of the test subjects were not stated. Patches (Finn chambers) were applied to the
volar aspect of the forearm and removed at 48 h. Reactions were scored at 1 h post-removal according to the following
scale: 0 (negative) to 3 (erythema, edema, and vesiculation). Punch biopsies were obtained. Most of the irritation
22
reactions were classified as mild to moderate. A statistically significant decrease (p < 0.01) in the epidermal density of
CD1+ cells and the length of dendritic processes of these cells (p < 0.001) was noted. There was also morphologic
evidence of cellular injury to Langerhans cells in the majority of biopsies.
Reiche et al.81
patch tested 152 female subjects (> 18 years old; 37 were atopic) with pelargonic acid in
propan-1-ol at concentrations of 10%, 20%, 40%, and 80%. The test substance (each concentration; 15 µl aliquot) was
soaked onto a filter paper disc in each Finn chamber (8 mm diameter) - applied to the right and left lower back. The
patches were removed at 47 h and reactions were scored at 48 h and 96 h. Propan-1-ol was applied to control sites.
Erythema was more severe at 48 h than at 96 h (p < 0.001). With the exception of 20% pelargonic acid, decreased
erythema with time was noted at each concentration. Changes at the skin surface (e.g., dryness, wrinkling, or necrosis),
however, increased with time at the higher concentrations. For example, at a concentration of 80% pelargonic acid,
surface changes were significantly greater at 96 h than at 48 h (p < 0.0001). The same was true for 40% pelargonic acid
(p = 0.0015).
In a study by Clemmensen et al.,82
the forearm skin of healthy volunteers was exposed in 2 different
cumulative skin irritation test models, a repeated open model (ROAT) and an exaggerated wash test model. In the
ROAT, 12 healthy volunteers (7 males, 5 females; mean age = 25.3 years) were tested with pelargonic acid at
concentrations of 10%, 20%, and 30% (vehicle = propanol). Sodium lauryl sulfate (SLS) was tested at concentrations
of 0.5%, 1.0%, and 2.0% (vehicle = sterile water). Applications were made to volar forearm skin of the right arm (SLS)
and left arm (pelargonic acid). Both substances were applied (10-min application) daily for 5 + 4 days (no applications
on weekend).
The wash test (24 healthy volunteers) involved the induction of irritation by 3 daily washings for 6 days and
the maintenance of the dermatitis by 2 daily washing for 12 days with pelargonic acid concentrations of 30%, 40%, and
50% (vehicle = propanol) or SLS concentrations of 5%, 10%, and 15% (vehicle = sterile water). Washing with
pelargonic acid involved 8 female and 4 male subjects (mean age = 27 years). Test areas were on the volar aspect of
each forearm and an oral hygiene sponge was used for washing. Erythema/edema were graded according to a total
scoring range of 0 to 15 (scores > 9 = very strong or caustic reaction).
In the ROAT, the maximum observed visual score of 12 was reported for 2 subjects tested with 30%
pelargonic acid. At the concentrations tested, pelargonic acid induced more irritation when compared to SLS and was
considered quite irritating. Dose-dependent healing and irritation scores approaching the pre-irritation values were
reported during follow-up at day 17. In the wash test model, all subjects treated with pelargonic acid achieved the
desired irritation score of 2 for at least one concentration of pelargonic acid. The maximum observed irritation score of
12 (1 subject,15% SLS) was observed at day 9.82
Suihko and Serup83
studied the applicability of fluorescence confocal laser scanning microscopy for in situ
imaging of irritant contact dermatitis caused by pelargonic acid using 12 healthy individuals (8 males, 4 males; 18 to 64
years old). Using Finn chambers (occlusive patches), the flexor side of the right and left forearm was exposed to 60 µl
of 10% (w/v) pelargonic acid in isopropanol solution and isopropanol vehicle. The Finn chambers were removed at 24
h post-application and reactions were scored according to the following scale: 0 (no visible reaction) to 4+ (intense
erythema with bullous formation).
Pelargonic acid induced five 2+ (moderate erythema with edema and papules) reactions and seven 1+ (mild
erythema with edema) reactions. The isopropanol vehicle induced five 1+ reactions and 5 +/- (faint, patchy erythema)
reactions. Microscopic findings indicated that pelargonic acid disturbed the epidermal intercellular borders, which were
described as blurred, thickened, and variably altered. These changes resulted from chemical damage to cellular
membranes. The authors noted that pelargonic acid might increase the size of individual keratinocytes, interpreted as a
result of intracellular disturbance with edema.83
Cetearyl Nonanoate
The skin irritation potential of cetearyl nonanoate, 97% pure, was evaluated using 52 volunteers (males and
females).36
The undiluted test substance (0.2 g) was applied to the upper back, and the application site was covered
23
with an occlusive patch for 48 h. Reactions were scored at 48 h and 72 h post-application. Skin reactions were not
observed in any of the subjects, and cetearyl nonanoate was classified as a non-irritant.
Neopentyl Glycol Diisononanoate
The skin irritation potential of undiluted neopentyl glycol diisononanoate was evaluated according to the
preceding test procedure using 52 volunteers (males and females).41
Neopentyl glycol diisononanoate was classified as
a non-irritant.
Ethyl Pelargonate
According to Opdyke,29
skin irritation was not observed after ethyl pelargonate was applied (5 min to 5 h) to
the skin of human subjects. At a concentration of 12% in petrolatum, ethyl pelargonate did not induce irritation in 48 h
closed patch tests involving human subjects.
Smith et al.84
evaluated the skin irritation potential of ethyl pelargonate using 10 healthy volunteers (4 males,
6 females; 39 to 70 years old). The test substance (20% [w/w] in petrolatum) was applied to the upper back for 24 h
using occlusive , 8 mm Finn chambers. The following served as controls: empty patch (negative control), petrolatum-
water (vehicle control), and 20% sodium lauryl sulfate (positive control). Skin irritation was not observed in any of the
subjects tested with ethyl pelargonate, and the same was true for negative and vehicle control test sites. The positive
control was irritating to the skin of 5 subjects.
Provocative Tests
In a study by Wahlberg and Maibach,85
75 patients with suspected allergic contact dermatitis (males and
females; 20 to 70 years old) were patch tested with pelargonic acid at concentrations of 5.0 %, 10.0 %, 20 % (in
propanol) and 100.0 % . Patches (Al-test® disc) were saturated with 0.04 ml of a test solution and applied to the upper
back for 48 h. Reactions were scored at 48 h and 96 h post-application. At a concentration of 20%, skin irritation was
observed in 93.9% of the 33 women tested and in 93.3% of the 48 men. All results from this study are summarized in
Table 5.
Wahlberg et al.86
studied the skin irritation potential of pelargonic acid using 100 hospitalized patients with
skin disease (54 males, 46 females; ages not stated). Pelargonic acid was tested at concentrations of 1.0, 5.0, 10.0, 20.0,
and 39.9% in 1-propanol. Patches (Al-test ® discs) saturated with the test solutions were applied to the upper back and
removed 48 h later. Reactions were scored at 1 h and 72 h post-removal. Results were reported as the lowest test
concentration that produced a reaction (individual scores not reported), and are summarized as follows: 1.0% pelargonic
acid (1 male; 2 females), 5.0% pelargonic acid (23 males; 9 females), 10.0% pelargonic acid (18 males; 22 females),
20.0% pelargonic acid (12 males; 13 females), and 39.9% pelargonic acid (all patients).
SKIN IRRITATION AND SENSITIZATION
Skin irritation and sensitization studies (normal subjects) on cetearyl nonanoate, ethylhexyl isononanoate,
neopentyl glycol diisononanoate, and product formulations containing isodecyl isononanoate (51.35%) or isononyl
isononanoate (3.552%) did not indicate a potential for irritation or sensitization.
Predictive Tests
Cetearyl Nonanoate
The skin sensitization potential of cetearyl nonanoate (97% pure) was evaluated in an RIPT using 106
volunteers (males and females).36
The undiluted test substance (0.2 g) was applied to the upper back under an occlusive
patch, for a total of 9 induction applications. Following a 2-week non-treatment period, each subject was challenged at
a new test site. Reactions were scored at 24 h and 72 h post-application. Cetearyl nonanoate did not induce skin
irritation nor allergic contact sensitization in any of the subjects.
Ethylhexyl Isononanoate
24
In an RIPT,67
the skin sensitization potential of undiluted ethylhexyl isononanoate was evaluated according to
the preceding test procedure using 52 volunteers. At the beginning of the test, mild skin irritation was observed in 10
subjects. It was concluded that ethylhexyl isononanoate did not indicate a potential for allergic contact sensitization.
Isodecyl Isononanoate
The skin irritation and sensitization potential of a makeup product containing 51.35% isodecyl isononanoate
was evaluated in an RIPT involving 101 normal subjects ( 18 to 65 years old).87
The 3-week, induction phase consisted
of 24-h semiocclusive patch applications to the upper back (between the scapulae). Following a 2-week, non-treatment
period, challenge patches were applied (24 h) to new sites on the back. Induction and challenge reactions were scored
immediately after patch removal according to the following scale: 0 (no visible skin reaction) to 4+ (erythema and
edema with vesiculation). Challenge reactions were also scored at 48 h and 72 h post-removal. Six subjects each had
either a ± (barely perceptible erythema) or 1+ (mild erythema) reaction during induction. At challenge, one subject had
a ± reaction at 48 h and 72 h and 2 subjects had a ± reaction at 72 h. It was concluded that the makeup product had no
dermal irritation or sensitization potential.
Isononyl Isononanoate
In a human repeated insult patch test (HRIPT),88
the skin irritation and sensitization potential of a lipstick
containing 3.552% isononyl isononanoate was evaluated. The number of subjects at the beginning of the study was not
stated; however, 53 subjects (ages not stated) satisfactorily completed the study. A modified Draize HRIPT procedure
was used. Semi-occlusive patches containing the lipstick (0.2 g) were applied to the back for 24 h during induction and
challenge phases. Challenge patch applications were made to previously untreated sites, and reactions were scored at
24 h and 72 h post-application. Skin reactivity was not observed in any of the 53 subjects during the study.
In another HRIPT (same procedure),89
the skin irritation and sensitization potential of another lipstick product
containing 3.128% isononyl isononanoate was evaluated. The number of subjects at the beginning of the study was not
stated; however, 97 subjects (ages not stated) satisfactorily completed the study. Skin reactivity was not observed in
any of the 97 subjects during the study.
Neopentyl Glycol Diisononanoate
The skin sensitization potential of undiluted neopentyl glycol diisononanoate was evaluated in an RIPT using
106 volunteers (males and females).41
The undiluted test substance (0.2 g) was applied to the upper back under an
occlusive patch, for a total of 9 induction applications. Following a 2-week non-treatment period, each subject was
challenged at a new test site. Reactions were scored at 24 h and 72 h post-application. Neopentyl glycol
diisononanoate did not induce skin irritation nor allergic contact sensitization in any of the subjects.
SKIN SENSITIZATION
Pelargonic acid esters are not sensitizers, based on the results of predictive human skin sensitization studies.
Negative results were reported for ethyl pelargonate and product formulations containing cholesteryl nonanoate or
branched-chain nonanoate esters.
Predictive Tests
Pelargonic Acid
According to Opdyke,29
pelargonic acid produced no sensitization reactions in 25 volunteers when tested at a
concentration of 12% (in petrolatum) in a maximization test.
Cetearyl Isononanoate
The skin sensitization potential of a liquid makeup remover containing 1.5% cetearyl isononanoate was
evaluated in a maximization test using 25 healthy adult volunteers (20 females, 5 males;18 to 65 years old).90
During
induction, the test substance (0.05 ml) was applied, for 48 h, under a Webril cotton cloth patch (15 mm disc) secured
with occlusive tape. Each induction application was preceded by a 24-h sodium lauryl sulfate (SLS) patch application
at the same site. Applications were made to the upper outer arm. Following a 10-day non-treatment period, a single
25
challenge application of the test substance (48 h) was made to a new site on the opposite upper arm of each subject.
Each challenge application was preceded by a 1-h SLS patch application. Reactions were scored at 48h or 72 h
according to the following scale: 0 (not sensitized) to 3 (strong sensitization). Contact allergy was not observed in any
of the subjects.
Cholesteryl Nonanoate
The skin sensitization potential of a lipstick containing 20.86% cholesteryl nonanoate was evaluated in a
maximization test using 28 healthy adult volunteers (10 males, 18 females; 21 to 57 years old).91
The test procedure
was identical to that stated in the preceding maximization test on a makeup remover containing ceteraryl isononanoate.
Contact allergy was not observed in any of the subjects.
Isotridecyl Isononanoate
In another study,92
the skin sensitization potential of a facial cream containing 4.3% isotridecyl isononanoate
was evaluated in a maximization test using 28 healthy volunteers (8 males, 20 females; 19 to 63 years old). The test
procedure was identical to that stated in the human maximization test on a makeup remover containing cetearyl
isononanoate earlier in the report text. Contact allergy was not observed in any of the subjects.
Isodecyl Isononanoate
The skin sensitization potential of a day cream containing 2.6% isodecyl isononanoate was evaluated in a
maximization test using 26 healthy volunteers (4 males, 22 females; 26 to 65 years old).93
The test procedure was
identical to that stated in the human maximization test on a makeup remover containing cetearyl
isononanoate earlier in the report text. Contact allergy was not observed in any of the subjects.
Isononyl Isononanoate
The skin sensitization potential of a cream eye shadow containing 24.66% isononyl isononanoate was
evaluated in a maximization test using 26 healthy volunteers (6 males, 20 females; 18 to 65 years old).94
The test
procedure was identical to that stated in the human maximization test on a makeup remover containing cetearyl
isononanoate earlier in the report text. Contact allergy was not observed in any of the subjects.
PEG-5 Isononanoate
The skin sensitization potential of an experimental formulation with the following composition was evaluated
in an RIPT using 53 volunteers: PEG-5 isononanoate (14.5%), water, trideceth-9, sodium hydroxide, and carbomer.42
Concentrations of the remaining components were not stated. The formulation (0.2 g) was applied, under an occlusive
patch, to the upper back of each subject for a total of 9 induction applications. After a 2-week non-treatment period, a
challenge patch was applied to a new site. Reactions were scored at 24 h and 72 h post-application. Reactions were not
observed during the study, and it was concluded that the formulation did not indicate a potential for allergic contact
sensitization.
Ethyl Pelargonate
According to Opdyke,29
results for 12% ethyl pelargonate in petrolatum were negative in 25 volunteers
evaluated in the maximization test.
Provocative Test
Isotridecyl Alcohol
Geier et al.95
evaluated the sensitization potential of isotridecyl alcohol (5% in petrolatum) using 229
dermatitis patients (mean age = 39.3 years). The patch application time was 1 or 2 days. All tests were read at least
until day 3. The test substance did not induce sensitization in any of the subjects tested.
EPIDERMAL PROLIFERATION AND APOPTOSIS
26
Pelargonic acid (80% in propanol) increased the density of proliferating keratinocytes and caused epidermal
cell apoptosis and a transient decrease in keratinocyte proliferation.
Willis et al.96
investigated alterations in the proliferative capacity of human epidermis following topical
exposure to pelargonic acid (80% [v/v] in propan-1-ol). Finn chambers containing the test substance were applied to the
volar aspect of the forearm of each of 10 healthy, non-atopic male volunteers for 48 h. Punch biopsies were removed
from each application site. Samples of normal skin were also obtained. Compared to the vehicle control, pelargonic
acid induced a statistically significant (p < 0.05) increase in the density of proliferating keratinocytes (i.e., increase in
mitotic activity).
Forsey et al.97
studied the effect of 80% pelargonic acid (in propan-1-ol) on Langerhans cells and on epidermal
proliferation and apoptosis. Punch biopsies were obtained from the volar forearm of 46 irritant contact dermatitis
patients (25 males, 21 females; age range = 18 to 62) and 10 healthy subjects, following application of the test
substance (Finn chambers) and vehicle control to the skin for up to 48 h. A higher number of Langerhans cells/mm
basement membrane in the patients, compared to controls, was reported. However, there was no difference in the
number of dendrites/Langerhans cell or in dendrite length. Pelargonic acid caused a decrease in keratinocyte
proliferation after 24 h of exposure, but a return to basal levels was observed after 48 h. Pelargonic acid induced
epidermal cell apoptosis after only 6 h of exposure, and dramatically decreased the Langerhans cell number after 24 h
and 48 h of exposure. Apoptosis was induced in over half of the Langerhans cells that were present after 24 h and 48 h.
EFFECT ON CD1a AND ICAM-1 EXPRESSION
Lindberg et al.98
investigated the possibility of differences in the interaction between different irritants
(pelargonic acid and SLS) and immunological parameters in the epidermis using 9 healthy volunteers. The reactions
were evaluated by immunohistochemistry using monoclonal antibodies directed against CD1a, CD3, and intercellular
adhesion molecule-1 (ICAM-1) molecules. Initially, occlusive patch tests (Finn chambers) involving the following 3
groups were conducted. In group 1 (2 males, 1 female; ages: 26 to 52 years), 2% SLS and 4% SLS in distilled water
(w/v) and distilled water alone were applied under occlusion for 24 h, and biopsies were obtained at 48 h. In group 2 (3
males; ages: 23 to 37 years), 20% pelargonic acid and 80% pelargonic acid in isopropanol (v/v), and isopropanol alone
were applied under occlusion for 24 h, and biopsies were obtained at 48 h. In group 3 (3 males; ages 24 to 25 years),
4% SLS in water and 80% pelargonic acid in isopropanol were applied under occlusion for 24 h; biopsies were obtained
immediately after Finn chamber removal.
At 48 h (groups 1 and 2), marked edema was observed at the 4% SLS site; this reaction was greater in severity
when compared to those induced by 20% and 80% pelargonic acid. At 24 h (group 3), the reactions to 4% SLS and
80% pelargonic acid were similar. Reactions were not induced by the distilled water or isopropanol vehicle. At both
24 h and 48 h, an exposure-related (SLS and pelargonic acid) increase in the number of CD3+ cells in the upper part of
the dermis was observed. A minor increase in CD3+ cells following exposure to distilled water, but not isopropanol,
was also observed at 48h. Few CD3+ cells were also identified in the epidermis following SLS and pelargonic acid
exposure.
Differences in ICAM-1 expression in the epidermis following SLS and pelargonic acid exposure were
observed. Following SLS exposure, an increase in ICAM-1+ keratinocytes at 24 h and 48 h was noted. A tendency
toward increased numbers of CD1a+ cells was noted at 48 h after treatment with 4% SLS. A definite decrease in the
number of CD1a+ cells was observed following exposure to 80% pelargonic acid. ICAM-1-reactivity was not detected
in the epidermis following exposure to 20% or 80% pelargonic acid. Increased levels of ICAM-1 expression were
observed in the epidermis following exposure to both water and isopropanol controls. In the control biopsies, 3 of 9
specimens had ICAM-1 reactivity (single cells or few keratinocytes). It was concluded that different irritants applied to
the skin surface may induce different responses in epidermis measured with markers for immunological components,
although the clinical picture indicates primary irritancy.98
CASE REPORTS Pelargonic Acid
27
Mathias et al.99
were authors of a case report on perioral leukoderma, simulating vitiligo, from the use of a
toothpaste containing cinnamic aldehyde. Pelargonic acid (10% and 20% aqueous solutions) was used as a positive
irritant control in patch tests that were performed on the 25-year-old female subject. Occlusive patches were applied for
48 h, and reactions were scored at 48 h and 96 h according to the method of the North American Contact Dermatitis
Group. Both solutions of pelargonic acid produced erythema and slight induration, confined to patch test sites.
Hyperpigmentation was observed at the sites of irritant reactions to pelargonic acid.
Cetearyl Isononanoate
In a case report by Le Coz and Bressieux,100
a 23-year-old female with a history of allergic contact dermatitis
developed acute dermatitis after application of a urea-based moisturizing cream containing cetearyl isononanoate. The
subject was patch tested (repeated open application test) with ingredients of the cream, each diluted to a concentration
identical to that in the product. Allergic reactions to the cream (day 2: ++; day 4: ++) and cetearyl isononanoate (day
2: negative; day 4: ++), both diluted to concentration of 4% in liquid mineral oil were reported. Patch test results for
4% cetearyl isononanoate were negative in 10 voluntary control subjects on days 2, 3, and 4.
Isononyl Isononanoate
In a case report by Goossens et al.,101
a 40-year-old, non-atopic female presented with contact cheilitis
following application of a lipstick product containing isononyl isononanoate in 2002. In 2007, she presented with
severe contact dermatitis on the eyelids following application of a new lipstick product containing isononyl
isononanoate to the eyelids. Patch test results for isononyl isononanoate were positive. Additional patch testing (patch
test chambers on forearm) was performed, and reactions were scored according to International Contact Dermatitis
Research Group criteria on days 2 and 4, and later. Strong (vesicular) positive reactions were observed at all tested
ethanolic dilutions of isononyl isononanoate, from 20% (actual use concentration in product) to 1%. The patient
developed severe edema of the entire test site. Patch test results for isononyl isononanoate (5% in ethanol) were
negative in 20 control subjects. Further patch testing in 2008 to identify possible cross-reactions did not yield further
positive reactions.
SUMMARY OF INFORMATION FROM EARLIER CIR SAFETY ASSESSMENTS
The CIR Final Safety Assessment on propylene glycol esters and diesters included propylene glycol dipelargonate with
a safe as used conclusion, but with a concern in the discussion regarding penetration enhancement with propylene
glycol dipelargonate. Butyl, cetyl, isobutyl, isocetyl, isopropyl, myristyl, and octyl stearate were reviewed as a group of
fatty acid esters and found safe as used. Decyl and isodecyl oleate were reviewed together and found safe as used,
based in part on the chemical similarity of the compounds and the corresponding similarities in the available animal
and human safety test data.
Propylene Glycol Esters and Diesters – including Propylene Glycol Dipelargonate
There were limited data on many of the propylene glycol esters and diesters. There were data indicating that
propylene glycol dicaprylate/dicaprate was a minimal dermal irritant and was not comedogenic. In the discussion, it
was noted that the caprylic (8 carbon chain)/capric (10 carbon chain) moiety is similar to the dipelargonate (9 carbon
chain) moiety. Propylene glycol dipelargonate was a penetration enhancer.
Overall, the Panel relied substantially on the prior reviews of the following ingredients previously reviewed to
demonstrate overall safety of this group:
propylene stearate for mutagenicity, chronic toxicity and skin sensitization;
caprylic/capric triglyceride for reproductive toxicity, chronic toxicity, and skin sensitization
coconut acid for chronic toxicity, tumor promotion, skin sensitization, phototoxicity, and
photosensitization
isostearic acid for skin sensitization, photosensitization, and phototoxicity
28
lauric, myristic, and oleic acids for reproductive toxicity, carcinogenicity, skin sensitization, and
photosensitization;
In the original safety assessment of isostearic acid, two reports that discussed metabolism were noted. One
study concluded that rat liver homogenate acyl coenzyme A synthetase was found to activate isostearic acid. In another
study that focused specifically on metabolism of iso-fatty acids versus straight-chain fatty acids, it was reported that
metabolism is similar by the mitochondrial and microsomal fractions of rat liver homogenate. The straight-chain fatty
acids are successively oxidized at the β carbon to yield two carbon fractions. The iso-fatty acids also follow that path,
but, in addition, are oxidized at the ω carbon to ultimately form three carbon dicarboxylic acids. The enzymes
catalyzing the ω-hydroxylation are present in the mitochondrial and microsomal fractions, whereas the enzymes
catalyzing further oxidation into carboxylic acids are in the soluble fractions of rat liver homogenate.
In the discussion, the Panel did note a concern about dermal penetration enhancement with propylene glycol
dipelargonate.
Butyl, cetyl, isobutyl, isocetyl, isopropyl, myristyl, and octyl (now ethyhexyl) stearate
Few data were available that demonstrated the metabolic fate of the iso forms compared to straight chain forms
beyond noting that aliphatic esters are hydrolyzed to the corresponding alcohol and fatty acid and further metabolized.
One study was provided in which isopropyl stearate, diluted in 9,10-3H2-labeled oleic acid, was given by gavage to
thoracic duct fistula rats. Radiolabel was found in lymph lipids, suggesting a dietary origin. Less than 10% of the
recovered radiolabel was in the form of the isopropyl ester and, conversely, over 95% of the radiolabel was in
triglycerides, leading to the suggestion that the isopropyl ester is hydrolyzed in the intestine and that the fatty acids thus
liberated are reesterified before distribution to lymph lipids.
Safety test data indicated low acute oral toxicity, no reproductive toxicity, and minimal skin irritation, but no
skin sensitization, phototoxicity, or photosensitization. The discussion noted the absence of data on comedogenicity.
Decyl and Isodecyl Oleate
These fatty acid esters have low acute oral toxicities, but few other toxicity data were available. They can be
minimal to moderate dermal irritants, but are not sensitizers in human and animal tests. No metabolic fate information
relevant to the esters was available.
SUMMARY
Pelargonic acid and nonanoate esters are cosmetic ingredients that function as a skin conditioning agent in
cosmetics. The following ingredients are reported as being used: butylene glycol diisononanoate, cetearyl
isononanoate, cetearyl nonanoate, cetyl isononanoate, cholesteryl nonanoate, diethylene glycol
diethylhexanoate/diisononanoate, dipentaerythrityl pentaisononanoate, ethylhexyl isononanoate, isodecyl isononanoate,
isononyl isononanoate, isotridecyl isononanoate, tridecyl isononanoate, ethylhexyl pelargonate, neopentyl glycol
diisononanoate, cetearyl nonanoate, cetyl isononanoate, dipentaerythrityl pentaisononanoate, neopentyl glycol
diisononanoate, PEG-2 diisononanoate, PEG-5 isononanoate, pentaerythrityl tetraisononanaote, polyglyceryl-20
octaisononanoate, and pentaerythrityl tetrapelargonate. Current ingredient use concentrations range from 0.01%
(cholesteryl nonanoate) to 74% (ethylhexyl isononanoate).
The following chemicals do not absorb significantly in the 250 to 400 nm range: neopentyl glycol
diisononanoate, cetyl nonanoate + stearyl nonanoate, trideceth-9 + PEG-5-isononanoate + water, glyceryl
triisononnoate + glyceryl diisononanoate, and ethylhexyl isononanoate.
29
Pelargonic acid, a fatty acid, is absorbed and then metabolized by beta-oxidation in the body. The
percutaneous absorption of isononyl alcohol was reported in an acute dermal toxicity study. Iso-fatty acids and
straight-chain fatty acids both are metabolized at the β carbon to yield two-carbon fractions by mitochondrial and
microsomal fractions of rat liver homogenate. Additionally, iso-fatty acids are oxidized at the ω carbon to ultimately
form three-carbon dicarboxylic acids. The enzymes catalyzing the ω-hydroxylation are present in the mitochondrial
and microsomal fractions, whereas the enzymes catalyzing further oxidation into carboxylic acids are in the soluble
fractions of rat liver homogenate.
Octanol-water partition coefficient (logP) and molecular weight data included in the safety assessment may be
used to predict the skin penetration potential of pelargonic acid and its esters/ester moieties. For example, the logP for
pelargonic acid is slightly >3 and its molecular weight is < 500, suggesting that it might be percutaneously absorbed.
The skin penetration enhancement effect of pelargonic acid on other chemicals has been demonstrated in vitro using
human stratum corneum and hairless rat skin.
An acute inhalation LC50 of 1.34 mg/L was reported for pelargonic acid in a study involving rats. Inhalation
exposure to isononanoic acid caused a concentration- dependent decrease in respiratory frequency in mice, and an
RD50 of 420 mg/m3 was reported. Few and no deaths were reported for mice/rats and guinea pigs, respectively,
following inhalation exposure to isononyl alcohol at a concentration of 21.7 mg/L.
Pelargonic acid and the esters for which data are available are not significant acute oral toxicants (LD50s > 1
g/kg) or acute dermal toxicants (highest LD50 reported = 9 g/kg).
Short-term oral dosing with pelargonic acid yielded an LOEL of 5,000 ppm in rats. Overt signs of toxicity
were not associated with higher doses. Limited numbers of rats given isononyl alcohol at 1 mmol/kg/day had no overt
signs of toxicity. The NOAEL for neopentyl glycol in rats was 100 mg/kg. Subchronic oral dosing with 1% ethyl
pelargonate (in diet) did not result in any remarkable gross or microscopic findings in rats. Repeated applications of
pelargonic acid (25% in mineral oil) to the skin of rabbits in a 28-day study did not cause death, and the random
inflammatory changes observed in various organs were described as spontaneous. In other studies, dermal application
of pelargonic acid to mice over a 3-day period did not cause death and a TDLo of 3,000 mg/kg was reported.
The ocular changes observed in a 28-day oral toxicity study (rats) on pelargonic acid were considered sporadic
and unrelated to treatment. In studies involving rabbits, pelargonic acid (0.1 ml) was severely irritating or mildly
irritating. Neither isononyl isononanoate nor ethylhexyl pelargonate (0.1 ml) induced ocular irritation in rabbits;
however, both cetearyl nonanoate and neopentyl glycol diisononanoate (0.1 ml) induced minimal ocular irritation and
isononyl alcohol (0.1 ml) induced marked ocular irritation. PEG-5 isononanoate (0.1 ml) induced transient ocular
reactions, but was not classified as an ocular irritant.
Pelargonic acid was a mild to severe skin irritant in rabbits and a severe skin irritant in guinea pigs, but was not
irritating to the skin of mice. The remaining studies involved rabbits only. Isononyl isononanoate and PEG-5
isononanoate were slightly/mildly irritating and ethyl pelargonate was moderately irritating to the skin; however,
isononyl alcohol induced marked skin irritation. Skin irritation was not observed following the application of cetearyl
nonanoate, cetearyl isononanoate, or ethylhexyl pelargonate.
Both pelargonic acid in methyl ester and pelargonic acid in propyl ester (both at 0.2% and 2.0%) were said to
have shown a sensitization tendency in a study examining the tissue response to pelargonic acid in the buccal mucosa of
the rat. In an RIPT, pelargonic acid (50% in corn oil) induced skin irritation, but not sensitization, in guinea pigs.
Pelargoinic acid esters (branched and straight-chain) were also irritants, but not sensitizers, in guinea pigs. Mouse
LLNA results were negative for 10% pelargonic acid and PEG-5 isononanoate, classified as a non-sensitizer.
Daily doses of pelargonic acid up to 1,500 mg/kg/day did not induce reproductive effects in inseminated
female rats. Results from other studies support pelargonic acid daily doses of 1500 mg/kg/day as the no-observable-
effect-level for maternal/developmental toxicity in rats. Two branched-chain nonanols (perhaps incorrectly identified
as isononanol) caused a marked degree of maternal and fetal toxicity in rats at daily doses of 7.5 and 10 mmol/kg/day
30
and slight fetal effects at 5 mg/kg/day doses. Neopentyl glycol at oral doses up to 1,000 mg/kg/day did not induce
reproductive effects.
While one mammalian cell assay of pelargonic acid was positive with metabolic activation, it was negative
without metabolic activation and all other bacterial, mammalian cell, and in vivo assays for pelargonic acid and the
following pelargonic acid esters were negative: cetearyl nonanoate, ethylhexyl isononanoate, neopentyl glycol
diisononanoate, and PEG-5 isononanoate. There was no evidence of gross skin tumors in mice dosed with undiluted
pelargonic acid in a dermal carcinogenicity study.
Pelargonic acid is a known skin irritant, based on and the results of both predictive and provocative human
skin irritation studies. In predictive tests, pelargonic acid induced skin irritation at concentrations ranging from 5% to
80%; ethyl pelargonate was a skin irritant at a concentration of 20%, but not 12%. Predictive human skin irritation test
results for undiluted cetearyl nonanoate and undiluted neopentyl glycol diisononanoate were negative, and the same
was true for predictive human skin irritation and sensitization studies on cetearyl nonanoate, ethylhexyl isononanoate,
and neopentyl glycol diisononanoate, all undiluted, and product formulations containing isodecyl isononanoate
(51.35%) and isononyl isononanoate (3.552%). Similarly, predictive human skin sensitization studies on 12%
pelargonic acid, 12% ethyl pelargonate, and formulations containing the following pelargonic acid esters were negative:
cetearyl isononanoate (1.5%), cholesteryl nonanoate (20.86%), isotridecyl isononanoate (4.3%), isodecyl isononanoate
(2.6%), isononyl isononanoate (24.66%), and PEG-5 isononanoate (14.5%). Results were negative for 5% isotridecyl
alcohol in a provocative human skin sensitization study.
In other human studies, pelargonic acid (80%) increased the density of proliferating keratinocytes and caused
epidermal cell apoptosis and a transient decrease in keratinocyte proliferation.
Patch testing with Pelargonic acid caused skin irritation and hyperpigmentation in a single case report. In
other case reports, a moisturizing cream containing cetearyl isononanoate induced contact dermatitis and a lipstick
containing 20% isononyl isononanoate induced contact cheilitis. Patch test results for 4% cetearyl isononanoate and
5% isononyl isononanoate were negative in healthy control subjects in these reports.
DISCUSSION
The CIR Expert Panel recognizes that the pelargonic acid branched esters included in this safety assessment
are not pure substances, but are always mixtures. Thus, the international nomenclature cosmetic ingredient (INCI) name
for each pelargonic acid branched ester actually refers to a mixture with general properties that, in many instances,
cannot be fully characterized. Regardless, the material, as supplied to the industry for use in cosmetics, is the same
material that is used in safety testing.
The Expert Panel noted the availability of acute inhalation toxicity data on pelargonic acid, isononanoic acid,
and isononyl alcohol, but not on any other of the ingredients that are being reviewed in this safety assessment.
However, in the absence of these data, the Panel determined that the ingredients included in this review can be used
safely in hair sprays, because the product particle size is not respirable. The Panel reasoned that the particle size of
aerosol hair sprays (around 38 µm) and pump hair sprays (>80 µm) is large compared to respirable particle sizes (≤10
µm).
Because animal sources of cetearyl isononanoate, cetyl isononanoate, cholesteryl nonanoate,
dihydrocholesteryl nonanoate, and isostearyl isononanoate have been reported, the Panel was also concerned with the
dangers inherent in using animal-derived ingredients, namely the transmission of infectious agents. The CIR Expert
Panel stressed that these ingredients must be free of detectable pathogenic viruses or infectious agents. Suppliers and
users of these ingredients must accept responsibility for assuring that these ingredients are risk-free. Tests to assure the
absence of a pathogenic agent in the ingredients, or controls to assure derivation from pathogen-free sources are two
approaches that should be considered.
31
The Expert Panel discussed that this group of ingredients contains both iso (branched) fatty acid esters and
straight-chain fatty acid esters. While the metabolic fate of branched esters, alcohols, and fatty acids is still unknown,
limited data on metabolism of iso forms versus straight-chain forms in rat liver homogenates indicated that both are
oxidized in a similar fashion, but that the iso form additionally may be oxidized at an additional hydrolysis site.
The Expert Panel also recognized that pelargonic acid and related ingredients, because of the skin penetration
enhancement property of pelargoinc acid in the presence of p-aminobenzoic acid or melatonin, could enhance the
penetration of similar chemicals, possibly cosmetic ingredients, through the skin. The Panel cautioned that care should
be taken in formulating cosmetic products that may contain these ingredients in combination with any ingredients
whose safety was based on their lack of dermal absorption data, or when dermal absorption was a concern.
Panel deliberations on the safety of pelargonic acid esters focused on current ingredient use concentration data
from industry in relation to human RIPT data on cosmetic products containing these ingredients. Current ingredient use
concentrations ranged from 0.01% (cholesteryl nonanoate) to 74% (ethylhexyl isononanoate). Ethylhexyl isononanoate
was a mild skin irritant, but a nonsensitizer, when tested undiluted. Similarly, cetearyl nonanoate and neopentyl glycol
diisononanoate, both undiluted, did not induce sensitization in human RIPTs. Other data indicate that the highest ester
concentration evaluated in a human RIPT was 51.35% isodecyl isononanoate in a makeup product (nonirritant and
nonsensitizer), which approaches the maximum use concentration of 59% for this ingredient. Based on negative results
for sensitization at high ingredient test concentrations, the Expert Panel reasoned that is not likely that the pelargonic
acid esters reviewed in this safety assessment would induce sensitization in the present practices of use.
CONCLUSION
The CIR Expert Panel concluded that butylene glycol diisononanoate, cetearyl isononanoate, cetearyl
nonanoate, cetyl isononanoate, cholesteryl nonanoate, diethylene glycol diethyl-hexanoate/diisononanoate,
dipentaerythrityl pentaisononanoate, ethylhexyl isononanoate, isodecyl isononanoate, isononyl isononanoate,
isotridecyl isononanoate, neopentyl glycol diisononanoate, PEG-2 diisononanoate, PEG-5 isononanoate, pentaerythrityl
tetraisononanaote, polyglyceryl-20 octaisononanoate, tridecyl isononanoate, ethylhexyl pelargonate, pentaerythrityl
tetrapelargonate, cellobiose octanonanoate, diethylene glycol diisononanoate, dihydrocholesteryl nonanoate, glycereth-7
diisononanoate, isostearyl isononanoate, phytosteryl nonanoate, propylene glycol diisononanoate, ethyl pelargonate,
isobutyl pelargonate, methyl pelargonate, neopentyl glycol dicaprylate/dipelargonate/dicaprate, and pelargonic acid are
safe as cosmetic ingredients in the present practices of use and concentration described in this safety assessment.1
1 Were ingredients in this group not in current use to be used in the future, the expectation is that they would
be used in product categories and at concentrations comparable to others in the group.
32
Table 1. Pelargonic Acid and its Nonanoate Esters15,15,15
Chemical Names Definition Functions in Cosmetics
pelargonic acid; nonanoic acid; nonoic acid;
nonylic acid; 1-octanecarboxylic acid; pelargic
acid; pergonic acid; CAS No. 112-05-0
an acid that conforms to the formula in
figure 1
fragrance ingredients; surfactants –
cleansing agents; surfactants –
emulsifying agents
butylene glycol diisononanoate; trade name:
cetiol FC
the diester of butylene glycol and
branched chain nonanoic acids
skin-conditioning agents – emollient;
skin-conditioning agents – occlusive;
viscosity increasing agents –
nonaqueous
cellobiose octanonanoate; α-D-glycopyranose, 4-
O-[2,3,4,6-tetrakis-O-(1-oxononyl)-β-D-
glucopyranosyl]- ,tetranonanoate; CAS No.
172585-66-9; trade name: alpha-D-cellobiose
octanonanoate
the octaester formed by the reaction of
α-D-cellobiose and nonanoic anhydride
viscosity increasing agents –
nonaqueous
cetearyl isononanoate; isononanoic acid,
cetyl/stearyl ether; tradenames: AEC cetearyl
isononanoate; cetiol SN; dub IN 1618; saboderm
CSN; and tegosoft CI
the ester of cetearyl alcohol and a
branched chain nonanoic acid
hair conditioning agents; skin-
conditioning agents – emollient
cetearyl nonanoate; trade name: SymMollient S
181598
the organic compound that conforms to
the formula in figure 1, where R
represents the cetearyl group
skin-conditioning agents – emollient
cetyl isononanoate; isononanoic acid, hexadecyl
ester; CAS No. 84878-33-1
the ester of cetyl alcohol with a
branched chain nonanoic acid
skin-conditioning agents – emollient
cholesteryl nonanoate; cholesterin pelargonate;
cholesteryl nonylate; cholesteryl pelargonate;
CAS No. 1182-66-7; trade name: yofco LC-CN
the ester of cholesterol and nonanoic
acid
not reported
Diethylene glycol
diethylhexanoate/diisononanoate;
the diester of a mixture of 2-
ethylhexanoic acid and isononanoic
acids and diethylene glycol
Hair conditioning agents; plasticizers;
skin-conditioning agents – emollient
diethylene glycol diisononanoate; isononanoic
acid, oxydi-2,1-ethanediyl ester; PEG-2
diisononanoate; CAS No. 106-01-4[sic];190282-
37-2
the diester of diethylene glycol and
isononanoic acid
hair conditioning agents; plasticizers;
skin-conditioning agents – emollient
dihydrocholesteryl nonanoate the ester of dihydrocholesterol and
nonanoic acid
skin-conditioning agents – emollient
33
Table 1. Pelargonic Acid and its Nonanoate Esters15,15,15
Chemical Names Definition Functions in Cosmetics
dipentaerythrityl pentaisononanoate; CAS No.
84418-63-3; trade name: dub vinyl
the pentaester of isononanoic acid with
a dimer of pentaerythritol
skin-conditioning agents – emollient;
viscosity increasing agents –
nonaqueous
ethylhexyl isononanoate; 2-ethyl-hexyl
isononanoate; 2-ethylhexyl isopelargonate; 2-
ethylhexyl 3,5,5-trimethyl-hexanoate [sic];
isononanoic Acid, 2-ethylhexyl ester; octyl iso-
nonanoate [sic]; CAS No.70969-70-9 [sic];
71566-49-9; trade names: AEC ethylhexyl
isononanoate; dermol 89; dub INO; ES 108109;
HallStar octyl isononanoate; isolanoate; pelemol
89; schercemol OISN
the ester of 2-ethyl-hexyl alcohol and a
branched chain nonanoic acid
skin-conditioning agents – emollient
glycereth-7 diisononanoate; PEG-7 glyceryl
ether diisononanoate; poly-ethylene glycol (7)
glyceryl ether diisononanoate; polyoxyethylene
(7) glyceryl ether diisononanoate; CAS No.
125804-15-1; trade name: dermol G-7DI
the diester of isononanoic acid and
glycereth-7
skin-conditioning agents – emollient;
solvents
isodecyl isononanoate; hexanoic acid, 3,5,5,-
trimethyl-, isodecyl ester [sic]; isodecyl 3,5,5-
trimethylhexanoate [sic]; isononanoic acid,
isodecyl ester; 3,5,5-trimethylhexanoic acid,
isodecyl ester [sic]; CAS Nos. 41395-89-5 and
59231-35-5 [sic]; trade names: AEC isodecyl
isononanoate; dermol 109; dub INID; KAK 109
the ester of branched chain decyl
alcohols and branched chain nonanoic
acid that conforms to the structure in
figure 1
skin-conditioning agents – emollient
isononyl isononanoate; hexanoic acid, 3,5,5-
trimethyl-, 3,5,5-tri-methylhexyl ester [sic];
isononanoic acid, isononyl ester; 3,5,5-
trimethylhexa-noic acid, 3,5,5-trimethylhexyl
ester [sic]; 3,5,5-trimethylhexyl-3,5,5-trimethyl-
hexanoate [sic]; CAS Nos. 42131-25-9 and
59219-71-5 [sic]; trade names: AEC isononyl
isononanoate; dermol 99; dub ININ; hatcol
5131; KAK 99; lanol 99; pelemol IN-2;
saboderm ISN; salacos 99
the ester of a branched chain nonyl
alcohol with a branched chain nonanoic
acid
skin-conditioning agents – emollient
isostearyl isononanoate; hexanoic acid, 3,5,5-
trimethyl-, isooctadecyl ester [sic]; CAS No.
90967-66-1[sic, 163564-45-2]; trade name: lanol
189
the ester of isostearyl alcohol and
isononanoic acid
skin-conditioning agents – emollient
34
Table 1. Pelargonic Acid and its Nonanoate Esters15,15,15
Chemical Names Definition Functions in Cosmetics
isotridecyl isononanoate; hexanoic acid, 3,5,5-
trimethyl-, isooctadecyl ester [sic]; isononanoic
acid, isotridecyl ester; isotridecyl 3,5,5-tri-
methylhexanoic acid [sic]; CAS Nos. 42131-27-
1 and 59231-37-7 [sic]; trade names: AEC
isotridecyl isononanoate; dub INI; KAK 129;
OriStar ITIN; salacos 913
the ester of isotridecyl alcohol and
isonona-noic acid
skin-conditioning agents – emollient
neopentyl glycol diisononanoate; CAS No.
137636-04-5 trade names: NPDIN; SymMollient
L 177205
the organic compound that conforms to
the structure in figure 1
skin-conditioning agents – emollient
PEG-2 diisononanoate; polyethylene glycol 100
diisononanoate; polyoxy-ethylene (2)
diisononanoate;
the polyethylene glycol diester of
isononanoic acid that conforms to the
structure in figure 1, where n has an
average value of 2
surfactants – emulsifying agents
PEG-5 isononanoate the organic compound that conforms
generally to the structure in figure 1,
where n has an average value of 5
surfactants – emulsifying agents
pentaerythrityl tetraisononanoate; 2,2-bis[[(1-
oxoisononyl)oxy]methyl]
-1,3-propanediyl isononanoate; isononanoic
acid, 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-
propanediyl ester; CAS No. 93803-89-5; trade
name: pelemol P-49
the tetraester of pentaerythritol and a
branched chain nonanoic acid. It
conforms generally to the structure in
figure 1, where RCO- represents the
isononanoic acid radical
skin-conditioning agents – occlusive;
viscosity increasing agents –
nonaqueous
phytosteryl nonanoate; trade name: yofco LC-
PN
the ester of phyto-sterol and nonanoic
acid
hair conditioning agents; skin-
conditioning agents – miscellaneous
polyglyceryl-20 octaisononanoate; trade name:
sunsoft Q-98U
the octaester of isononanoic acid and
polyglycerin-20
surfactants – cleansing agents;
surfactants – emulsifying agents;
surfactants – solubilizing agents
propylene glycol diisononanoate; isononanoic
acid, 1-methyl-1,2-ethanediyl ester; CAS No.
125804-17-3; trade names: AEC propylene
glycol diisononanoate; dermol PGDI
the diester of propylene glycol and
branched chain nonanoic acids
skin-conditioning agents – occlusive;
viscosity increasing agents –
nonaqueous
tridecyl isononanoate; hexanoic acid, 3,5,5-
trimethyl-, tridecyl ester;
isononanoic acid [sic], tridecyl ester;
3,5,5-trimethylhexanoic acid, tridecyl ester [sic];
CAS No. 125804-18-4; trade name: dermol 139
the ester of tridecyl alcohol and
isononanoic acid that conforms to the
structure in figure 1
skin-conditioning agents – emollient
35
Table 1. Pelargonic Acid and its Nonanoate Esters15,15,15
Chemical Names Definition Functions in Cosmetics
ethylhexyl pelargonate; 2-ethylhexyl
pelargonate; nonanoic acid, w-ethylhexyl ester;
octyl pelargonate; CAS No. 59587-44-9; trade
names: AEC ethylhexyl pelargonate; bernel ester
OPG; crodamol OPG; dub PEO; jeechem OPG;
pelemol OPG; schercemol OPG ester
ester of 2-ethylhexyl alcohol and
pelargonic acid that conforms to the
structure in figure 1
Skin-conditioning agents – emollient
ethyl pelargonate; ethyl nonanoate; nonanoic
acid, ethyl ester; CAS No. 123-29-5
ester of ethyl alcohol and pelargonic
acid that conforms to the structure in
figure 1
fragrance ingredients; hair conditioning
agents; skin-conditioning agents –
emollient
isobutyl pelargonate; isobutyl nonanoate; 2-
methylpropyl nonanoate; nonanoic acid, isobutyl
ester; nonanoic acid, 2-methypropyl ester; CAS
No. 30982-03-7; trade name: AEC isobutyl
pelargonate
ester of isobutyl alcohol and pelargonic
acid that conforms to the structure in
figure 1
fragrance ingredients; skin-conditioning
agents – emollient
methyl pelargonate; methyl nonanoate; nonanoic
acid, methyl ester; pelargonic acid methyl ester;
CAS No. 1731-84-6
ester of methyl alcohol and pelargonic
acid that conforms to the structure in
figure 1
fragrance ingredients; skin-conditioning
agents – emollient
neopentyl glycol
dicaprylate/dipelargonate/dicaprate
diester of neopentyl glycol and a blend
of caprylic, pelargonic, and capric acids
skin-conditioning agents – emollient;
viscosity increasing agents –
nonaqueous
pentaerythrityl tetrapelargonate; 2,2-bis[[(1-
oxononyl)oxy]methyl]-1,3-propanediyl
nonanoate; nonanoic acid, 2,2-bis[[(1-
oxononyl)oxy]methyl]-1,3-propanediyl ester;
CAS No. 14450-05-6; trade name: pelemol PTP
tetraester of pentaerythritol and
pelargonic acid that conforms to the
structure in figure 1
binders; skin-conditioning agents –
occlusive; viscosity increasing agents –
nonaqueous
36
Table 2. Chemical and Physical Properties
Property Value Reference
Pelargonic Acid
Form
Oily, colorless liquid Lewis102
Molecular weight 158.24 STN17
Density 0.9055 @ 20/4C
0.9839 g/cm3 @ 20C
0.921 ± 0.06 g/cm3 @ 20C
(calculated value)
Lewis102
STN17
Solubility
Miscible with water and methanol
Very slightly soluble in water
Committee of Revision of the
United States Pharmacopeial
Convention103
Lewis102
Refractive index 1.4456 @ 20C and 589.3 nm STN17
Vapor pressure 8.67E-03 Torr (calculated) ACD Labs104
Melting point 12C
12.3 C
Lewis102
STN17
Freezing point 12.24C Lewis102
Boiling point
254.4C @ 760 Torr
254.9 ± 3C @ 760 Torr (calculated)
ACD Labs104
Flash point 100.0 ± 0C (calculated) ″
Enthalpy of vaporization 52.03 ± 3.0 kJ/mol (calculated) ″
pKa 4.78 ± 0.10 (calculated) ″
logP 3.434 ± 0.184 @ 25C (calculated) ″
Cetearyl Isononanoate (Tegosoft CI)
Form Yellowish liquid Evonik Industries105
Refractive index 1.4450 to 1.4500 (specification) Evonik Industries106
Density 0.854 to 0.858 g/ml (specification);
≈ 0.85 g/cm3 @ 68°F
Evonik Industries105, 106
Solubility Insoluble in water Evonik Industries105
Viscosity, according to Höppler
(mPas)
≈ 16 @ 25°C Evonik Industries107
Volatility 0% in water Evonik Industries 105
37
Table 2. Chemical and Physical Properties
Property Value Reference
Melting temperature < 59°F Evonik Industries105
Flash point >212°F Evonik Industries105
Solidifications point ≤ 15.0°C (specification) Evonik Industries106
Hydroxyl value ≤ 1.0 mg KOH/g (specification) ″
Iodine value ≤ 1.0 g l/100g (specification) ″
Acid value ≤ 0.2 mg KOH/g (specification) ″0
Saponification value 140.0 to 146.0 mg KOH/g
(specification)
″
Heavy metals content 20 ppm maximum (Cu; Pb; Sn; Pt;
Pd; Hg; As; Cd; Ni); < 1 ppm (Hg;
As; Cd; Ni respective)
Evonik Industries108
Cellobiose Octanonanoate
Molecular weight 1464.08 STN17
Density
1.05 ± 0.1 g/cm
3 @ 20C (calculated) ″
Vapor pressure 0 Torr @ 25C (calculated) ″
Boiling point 1115.1 ± 65C @ 760 Torr
(calculated)
″
Flash point 371.9 ± 34.3 C (calculated) ″
Enthalpy of vaporization 164.52 ± 3.0 kJ/mol @ 760 Torr
(calculated)
″
log P 32.470 ± 0.860 @ 25C (calculated ) ″
Cholesteryl Nonanoate
Molecular weight 526.88 (calculated) STN17,17
Density
0.97 ± 0.1 g/cm3 @ 20C and 760
Torr (calculated)
″
Optical rotation - 30@ concentration of 1.0 g/100 ml
in chloroform
″
Vapor pressure 2.77E-13 Torr @ 25C (calculated) ″
Melting point 80C ″
Boiling point 576.3 ± 29C @ 760 Torr
(calculated)
″
38
Table 2. Chemical and Physical Properties
Property Value Reference
Flash point 300.8 ± 11.8 C (calculated) STN17
Enthalpy of vaporization 86.30 ± 3.0 kJ/mol @ 760 Torr
(calculated)
″
logP 14.4245 ± 0.299 @ 25C (calculated) ″
Isodecyl Isononanoate
Refractive index 1.437 to 1.439 @ 25C
(specification)
Nikitakis and McEwen109
Specific gravity 0.852 to 0.858 @ 25/25C
(specification)
″
Acid value 1.0 maximum (specification) ″
Saponification value 175 to 192 (specification) ″
Iodine value 0.5 maximum (specification) ″
Isononyl Isononanoate
Refractive index 1.4340 to 1.4360 @ 25C
(specification)
Nikitakis and McEwen109
Specific gravity 0.849 to 0.855 @ 25/25C
(specification)
″
Acid value 1.0 maximum (specification) ″
Saponification value 192 to 202 (specification) ″
Iodine value 0.5 maximum (specification) ″
Isononyl Isononanoate (Tegosoft INI)
Form Colorless to slightly yellow liquid Evonik Industries110
Density 0.865 g/cm3 at 71.60°F ″
Solubility Insoluble in water ″
Viscosity, dynamic 5.5 mPa.s @ 20°C ″
Boiling temperature 273.20 to 280.40°F @ 1.3 hPa ″
Flash point 305.60°F ″
Hydroxyl value ≤ 5.0 mg KOH/g (specification) Evonik Industries111
Iodine value ≤ 0.50 g l/100 g (specification) ″
Acid value ≤ 0.20 mg KOH/g (specification) ″
39
Table 2. Chemical and Physical Properties
Property Value Reference
Saponification value 185 to 200 mg KOH/g
(specification)
Evonik Industries111
Water content ≤ 0.30 % (specification) ″
Heavy metals content 20 ppm maximum (Cu; Pb; Sn; Pt;
Pd; Hg; As; Cd; Ni); < 1 ppm (Hg;
As; Cd; Ni respective)
Evonik Industries112
Isotridecyl Isononanoate
Refractive index 1.433 to 1.445 @ 25C
(specification)
Nikitakis and McEwen109
Specific gravity 0.859 to 0.861 @ 25/25C
(specification)
″
Acid value 1.0 maximum (specification) ″
Saponification value 155 to 165 (specification) ″
Iodine value 0.5 maximum (specification) ″
Ethylhexyl Pelargonate
Molecular weight 270.45 STN 17
Density 0.864 ± 0.06 g/cm3
@ 20°C ″
Mass intrinsic solubility 0.0022 g/l @ 25°C (calculated) ″
Molar intrinsic solubility 0.0000081 mol/l @ 25°C
(calculated)
″
Boiling Point 311.8 ± 10.0°C @ 760 Torr
(calculated)
″
Vapor pressure 5.49E-04 Torr @ 25°C (calculated) ″
Enthalpy of vaporization 55.28 ± 3.0 kJ/mol @ 760 Torr
(calculated)
″
Flash point 144.1 ± 8.8°C (calculated) ″
logP 7.432 ± 0.212 @ 25°C (calculated) ″
Ethyl Pelargonate
Molecular weight 186.29 STN17
Density 0.872 ± 0.06 g/cm3
@ 20°C
(calculated)
″
Refractive index 1.43367 @ 15°C ″
Mass intrinsic solubility 0.17 g/l @ 25°C (calculated) ″
40
Table 2. Chemical and Physical Properties
Property Value Reference
Molar intrinsic solubility 0.0092 mol/l @ 25°C (calculated) STN17
Boiling point 225.5 to 227.5°C; 220.0 ± 0°C @
760 Torr (calculated)
″
Melting point -36.7°C ″
Vapor pressure 1.16E-01 Torr @ 25°C (calculated) ″
Enthalpy of vaporization 45.64 ± 3.0 kJ/mol @ 760 Torr
(calculated)
″
Flash point 94.4 ± 0°C (calculated) ″
logP 4.428 ± 0.206 @ 25°C (calculated) ″
Isobutyl Pelargonate
Molecular weight 214.34 (calculated) STN17
Density 0.867 ± 0.06 g/cm3
@ 20°C
(calculated)
″
Mass intrinsic solubility 0.041 g/l @ 25°C (calculated) ″
Molar intrinsic solubility 0.00019 mol/l @ 25°C (calculated) ″
Boiling point 248.9 ± 8°C @ 760 Torr
(calculated)
″
Vapor pressure 2.36E-02 Torr @ 25°C (calculated) ″
Enthalpy of vaporization 48.61 ± 3.0 kJ/mol @ 760 Torr
(calculated)
″
Flash point 104.7 ± 8.3°C (calculated) ″
logP 5.307 ± 0.212 @ 25°C (calculated) ″
Methyl Pelargonate
Molecular weight 172.26 (calculated) STN 17
Density 0.8655 g/ cm3 @ 25°C; 0.874 ± 0.06
g/cm3 @ 20°C and 760 Torr
(calculated)
″
Refractive index 1.4205 @ 20°C and 589.3 nm;
1.41395 @ 25°C and 589.3 nm
″
Mass intrinsic solubility 0.36 g/l @ 25°C (calculated) ″
Molar intrinsic solubility 0.0021 mol/l @ 25°C (calculated) ″
Boiling point 213.5 and 122.0°C; 210.3 ± 3°C @
760 Torr (calculated)
″
41
Table 2. Chemical and Physical Properties
Property Value Reference
Vapor pressure 1.93E-01 Torr @ 25°C (calculated) STN17
Enthalpy of vaporization 44.66 ± 3.0 kJ/mol @ 760 Torr
(calculated)
″
Flash point 84.4 ± 0°C (calculated) ″
logP 3.896 ± 0.205 @ 25°C (calculated) ″
Pentaerythrityl Tetrapelargonate
Molecular weight 697.04 (calculated) STN17
Density 0.969 ± 0.06 g/cm3
@ 20°C and 760
Torr (calculated)
″
Mass intrinsic solubility 0.00000077 g/l @ 25°C (calculated) ″
Molar intrinsic solubility 0.0000000011 mol/l @ 25°C
(calculated)
″
Boiling point 699.1 ± 50°C @ 760 Torr
(calculated)
″
Melting point 12°C ″
Vapor pressure 2.16E-19 Torr @ 25°C (calculated) ″
Enthalpy of vaporization 102.35 ± 3.0 kJ/mol @ 760 Torr
(calculated)
″
Flash point 273.5 ± 30.2 °C (calculated) ″
LogP 14.879 ± 0.360 @ 25°C (calculated) ″
Isononanoic Acid
Molecular weight 158.24 STN17
Density 0.919 ± 0.06 g/cm3 @ 20°C and 760
Torr (calculated)
″
Refractive index 1.4304 @ @ 21°C and 589.3 nm ″
Mass intrinsic solubility 0.52 g/l @ 25°C (calculated) ″
Molar intrinsic solubility 0.0033 mol/l @ 25°C (calculated) ″
Boiling point 248°C @ 765 Torr and 253.4 ± 8°C
@ 760 Torr (calculated)
″
Melting point 3 to 5ºC ″
Vapor pressure 5.70E-03 Torr @ 25°C (calculated) ″
42
Table 2. Chemical and Physical Properties
Property Value Reference
Enthalpy of vaporization 54.04 ± 6.0 kJ/mol @ 760 Torr
(calculated)
STN17
Flash point 129.7 ± 6.9°C (calculated) ″
LogP 3.250 ± 0.194 @ 25ºC ″
Isononyl Alcohol
Boiling point 100°C @ 13 Torr STN17
Melting point 64 to 65ºC ″
LogP 3.22 SRC113
Isotridecyl Alcohol
LogP 5.19 (calculated) SRC113
Neopentyl glycol
Molecular weight 104.149 STN114
Density 1.1 g/cm3 National Institute for Occupational
Safety and Health (NIOSH)115
Impurities Neopentyl glycol formic acid ester
and neopentyl glycol isolactic acid
ester
Organisation for Economic Coop-
eration and Development (OECD) 43
Water solubility 190 g/100 ml @ 25ºC (65%) ″
Melting point 127 ºC (solvent = benzene) STN 2009b114
“
Boiling point 206 ºC @ 747 Torr ″
Flash point 107ºC NIOSH 2010115
Autoignition temperature 388 ºC ″
Explosive limits 1.1 to 11.4 vol% in air ″
Vapor pressure 0.00217522 to 0.0551305 Torr @
10.74 to 38.14ºC
30 mmHg @140ºC and 760 mmHg
@ 211ºC
″
OECD 43
Enthalpy of fusion 4590 J/mol ″
Enthalpy of vaporization 87,320 J/mol @ 25.24ºC ″
Enthalpy of phase transition 14,100 J/mol ″
43
Table 2. Chemical and Physical Properties
Property Value Reference
Heat capacity 193.48 to 202.21 J/mol *K @ 31.85
to 39.35ºC
″
Thermal decomposition Occurs at > 120ºC in strong base. ″
Thermal decomposition products Methanol, isobutanol, isobutyl
aldehyde, formaldehyde, etc.
″
LogP 0.12 @25ºC (measured) OECD43
44
Table 3. Current Cosmetic Product Uses and Concentrations of Nonanoates and Pelargonic Acid22,23
Product Category
(FDA 2009)
2009 uses (total number of
products in category; FDA 2009)
2009 concentrations
(Personal Care Products Council
2009) (%)
butylene glycol diisononanoate
Skin care products
Skin cleansing creams, lotions, liquids, and pads - 17
Total uses/ranges for butylene glycol diisononanoate - 17
cetearyl isononanoate
Eye makeup
Eyeliner 2 (684) -
Eye shadow 5 (1196) 0.05
Eye lotion 4 (177) -
Eye makeup remover 1 (131) -
Other 3 (288) -
Fragrance products
Other 3 (399) 27 to 50
Noncoloring hair products 1 (1097)
Tonics, dressings, etc. -
Makeup
Blushers 1(539) 8
Face powders 2 (613) 0.05 to 11
Foundations 4 (635) 10
Lipstick 1 (1912) -
Makeup bases 1 (164) -
Other 3 (406 12
Nail care products
Creams and lotions 1 (17) -
Other 1 (124) -
Personal hygiene products
Other 2 (514) -
Shaving products
Aftershave lotion 1 (395) 3 to 6
Preshave lotions 1 (27) -
Skin care products
Skin cleansing creams, lotions, liquids, and pads 10 (1368) 2 to 3
Face and neck lotions 12 (1195) 0.07 to 8
Body and hand lotions 14 (1513) 3 to 5
Foot powders and sprays 1 (48) -
Moisturizers 29 (2039) 2
Night creams and lotions 6 (343) 2
Paste masks (mud packs) 1 (418) -
Table 3. Current Cosmetic Product Uses and Concentrations of Nonanoates and Pelargonic Acid – cont’d
45
Product Category
(FDA 2009)
2009 uses (total number of
products in category; FDA 2009)
2009 concentrations
(Personal Care Products Council
2009) (%)
Other 9 (1244) -
Suntan products
Indoor tanning preparations 3 (200) -
Other 1 (62) -
Total uses/ranges for cetearyl isononanoate 123 0.05 to 50
cetearyl nonanoate
Skin care products
Body and hand lotions - 3
Total uses/ranges for cetearyl nonanoate - 3
cetyl isononanoate
Eye makeup
Eye lotion - 1
Noncoloring hair products
Tonics, dressings, etc. - 1
Skin care products
Body and hand lotions - 3
Moisturizers - 5
Other - 1
Total uses/ranges for cetyl isononanoate - 1 to 5
cholesteryl nonanoate
Eye makeup
Eye lotion 2 (117) -
Other 1 (288) -
Noncoloring hair products
Conditioners - 0.01
Shampoos - 0.01
Makeup
Lipstick - 20 to 30
Skin care products
Face and neck lotions - 0.04
Moisturizers - 0.06
Paste masks (mud packs) - 0.03
Hair coloring products -
Dyes and colors 13 (2481) -
Makeup
Lipstick 1 (1912) -
Makeup bases 1 (164) -
Table 3. Current Cosmetic Product Uses and Concentrations of Nonanoates and Pelargonic Acid – cont’d
46
Product Category
(FDA 2009)
2009 uses (total number of
products in category; FDA 2009)
2009 concentrations
(Personal Care Products Council
2009) (%)
Skin care products
Face and neck lotions 8 (1195) -
Moisturizers 3 (2039) -
Paste masks (mud packs) 6 (418) -
Skin fresheners 1 (285) -
Other 2 (1244) -
Total uses/ranges for cholesteryl nonanoate 38 0.01 to 30
diethylene glycol diethylhexanoate/diisononanoate
Fragrance products
Powders 5 (278) 19
Makeup
Foundations 1 (635) 18
Lipstick 9 (1912) -
Other 1 (406) -
Total uses/ranges for diethylene glycol
diethylhexanoate/diisononanoate
16 18 to 19
dipentaerythrityl pentaisononanoate
Makeup
Lipstick - 9
Nail care products
Nail polish and enamel - 13
Total uses/ranges for dipentaerythrityl
pentaisononanoate
- 9 to 13
ethylhexyl isononanoate
Eye makeup
Eye shadow 3 (1196) 7 to 65
Eye lotion 2 (177) 0.8
Eye makeup remover 1 (131) -
Other 2 (288) 12
Fragrance products
Other 3 (399) 2 to 5
Noncoloring hair products
Conditioners - 1
Rinses - 0.8
Tonics, dressings, etc. 3 (1097) -
Other 1 (716) 8
Makeup
Blushers 1 (539) 7
Face powders - 3
Table 3. Current Cosmetic Product Uses and Concentrations of Nonanoates and Pelargonic Acid – cont’d
47
Product Category
(FDA 2009)
2009 uses (total number of
products in category; FDA 2009)
2009 concentrations
(Personal Care Products Council
2009) (%)
Foundations 2 (635) 3
Lipstick 9 (1912) -
Fixatives 1 (38) -
Other 2 (406) 31 (in a face highlighter)
Personal hygiene products
Other 1 (514) -
Shaving products
Aftershave lotion 2 (395) 1
Skin care products
Skin cleansing creams, lotions, liquids, and pads 1 (1368) 0.8 to 2
Face and neck lotions 5 (1195) 0.04 to 6
Body and hand lotions 31 (1513) 0.04 to 74
Body and hand sprays - 18
Moisturizers 14 (2039) 2
Night creams and lotions 5 (343) 0.02
Other 3 (1244) 0.08
Suntan products
Suntan gels, creams, and liquids 1 (156) 7
Indoor tanning preparations 22 (200) 0.07 to 1
Other 1 (62) 0.03
Total uses/ranges for ethylhexyl isononanoate 116 0.02 to 74
isodecyl isononanoate
Eye makeup
Eye shadow 2 (1196) 21
Eye lotion - 6
Eye makeup remover - 10
Noncoloring hair care products
Conditioners - 2
Other 1 (406) -
Makeup
Blushers 6 (539) 22 to 26
Foundations 1 (635) 59
Lipstick - 0.05 to 18
Rouges - 13
Skin care products
Face and neck lotions 5 (1195) -
Moisturizers 4 (2039) -
Night creams and lotions 1 (343) -
Paste masks (mud packs) 2 (418) 2
Table 3. Current Cosmetic Product Uses and Concentrations of Nonanoates and Pelargonic Acid – cont’d
48
Product Category
(FDA 2009)
2009 uses (total number of
products in category; FDA 2009)
2009 concentrations
(Personal Care Products Council
2009) (%)
Other 2 (1244) -
Suntan products
Suntan gels, creams, and liquids 1 (156) -
Other 1 (62) 5
Total uses/ranges for isodecyl isononanoate 26 0.05 to 59
isononyl isononanoate
Bath products
Oils, tablets, and salts - 15
Soaps and detergents - 8 to 10
Eye makeup
Eyebrow pencil - 2
Eye shadow 24(1196) 2 to 18
Eye lotion 8 (177) 3 to 26
Eye makeup remover 2 (131) -
Other 13 (288) 6 to 12 (12% in a concealer)
Fragrance products
Perfumes 4 (569) 26 to 42
Other 2 (399) 21 to 46
Noncoloring hair care products
Other 1 (716) -
Conditioners - 0.08
Sprays/aerosol fixatives - 0.4
Rinses - 0.03 to 1
Tonics, dressings, etc. - 7
Hair coloring products
Bleaches - 33
Makeup
Blushers 23 (539) 4 to 17
Face powders 12 (613) 2 to 15
Foundations 28 (635) 3 to 27
Leg and body paints 3 (29) 4 to 57
Lipstick 28 (1912) 8 to 50
Makeup bases 3 (164) 3 to 7
Rouges 3 (99) 12
Makeup fixatives 3 (38) -
Other 12 (406) 4 to 6 (4% in a concealer)
Nail care products
Nail extenders - 0.4
Nail polish and enamel removers - 5
Table 3. Current Cosmetic Product Uses and Concentrations of Nonanoates and Pelargonic Acid – cont’d
49
Product Category
(FDA 2009)
2009 uses (total number of
products in category; FDA 2009)
2009 concentrations
(Personal Care Products Council
2009) (%)
Personal hygiene products
Deodorants (underarm) 1 (540) 3
Other 1 (514) -
Shaving products
Aftershave lotion 2 (395) 3 to 4
Preshave lotions - 22
Skin care products
Skin cleansing creams, lotions, liquids, and pads 11 (1368) 0.04 to 21
Face and neck lotions 39 (1195) 0.05 to 17
Face and neck sprays - 6
Body and hand lotions 29 (1513) 5 to 50
Foot powders and sprays - 3
Moisturizers 48 (2039) 3 to 13
Night creams and lotions 10 (343) 2 to 11
Paste masks (mud packs) 2 (418) 2 to 64
Skin fresheners 1 (285) -
Other 16 (1244) 1 to 21
Suntan products
Suntan gels, creams, and liquids 2 (156) 2 to 9
Indoor tanning preparations 8 (200) 0.3 to 3
Other 4 (62) 0.08 to 21
Total uses/ranges for isononyl isononanoate 343 0.03 to 64
isotridecyl isononanoate
Eye makeup
Eye shadow - 0.7
Noncoloring hair products
Conditioners - 3
Makeup
Blushers 15 (539) 4
Face powders 6 (613) 10
Foundations 10 (635) 0.8 to 9
Lipstick 19 (1912) 10
Makeup bases - 5 to 7
Rouges - 4
Other 3 (406) 5
Skin care products
Face and neck lotions 2 (1195) -
Body and hand lotions 1
Moisturizers 4 (2039) 11
Table 3. Current Cosmetic Product Uses and Concentrations of Nonanoates and Pelargonic Acid – cont’d
50
Product Category
(FDA 2009)
2009 uses (total number of
products in category; FDA 2009)
2009 concentrations
(Personal Care Products Council
2009) (%)
Night creams and lotions 2 (343) -
Other 1 (1244) 5 to 51
Suntan products -
Suntan gels, creams, and liquids - 0.8
Total uses/ranges for isotridecyl isononanoate 62 0.7 to 51
neopentyl glycol diisononanoate
Skin care products
Skin cleansing creams, lotions, liquids, and pads - 1
Total uses/ranges for neopentyl glycol diisononanoate - 1
PEG-2 diisononanoate
Nail care products
Creams and lotions - 2
Total uses/ranges for PEG-2 diisononanoate - 2
PEG-5 isononanoate
Skin care products
Skin cleansing creams, lotions, liquids, and pads - 1
Total uses/ranges for PEG-5 isononanoate - 1
pentaerythrityl tetraisononanoate
Eye makeup
Eye lotion - 2
Skin care products
Body and hand lotions - 1
Total uses/ranges for pentaerythrityl
tetraisononanoate
- 1 to 2
polyglyceryl-20 octaisononanoate
Skin care products
Skin cleansing creams, lotions, liquids, and pads - 3
Total uses/ranges for polyglyceryl-20
octaisononanoate
- 3
tridecyl isononanoate
Makeup
Foundations 1 (635) 9
Total uses/ranges for tridecyl isononanoate 1 9
ethylhexyl pelargonate
Hair coloring products
Dyes and colors - 5
Eye makeup
Eye shadow - 2
Table 3. Current Cosmetic Product Uses and Concentrations of Nonanoates and Pelargonic Acid – cont’d
51
Product Category
(FDA 2009)
2009 uses (total number of
products in category; FDA 2009)
2009 concentrations
(Personal Care Products Council
2009) (%)
Makeup
Blushers 1 (539) -
Foundations 1 (635) 25
Skin care products
Skin cleansing creams, lotions, liquids, and pads 1 (1368) 2
Body and hand lotions - 4
Total uses/ranges for ethylhexyl pelargonate 3 2 to 25
pentaerythrityl tetrapelargonate
Noncoloring hair care products
Tonics, dressings etc. - 2
Total uses/ranges for pentaerythrityl tetrapelargonate - 2
Table 4. Skin Irritation and Sensitization Studies on Pelargonic Acid, Nonanoate Esters, and Related Chemicals
52
Test Substance Subjects Tested Test Protocol Results References
Predictive Tests – Skin Irritation
Pelargonic Acid
0.01 M, 0.1 M,
0.5 M and 1.0 M
(in propanol)
20 male subjects
(ages not stated): 0.5
M application (10
subjects) and 1.0 M
(10 subjects); 0.01 M
and 0.1 M
intradermal injections
(5 subjects)
24 h Al-test® patch
application to
interscapular area, 10
applications
total/dose (0.04 ml
volume; application
area [cm2] not stated);
10 intradermal
injections (0.1
ml/injection) total
/dose
Erythematous reactions: 7
subjects (0.5 M), 10
subjects (1.0 M), and 5
subjects (0.01 and 0.1 M)
Stillman et al.72
5%, 10%, 20%,
and 39.9% (in
propanol)
116 male subjects (21
to 55 years old)
48 h patch (Al-test®
disc) application to
upper back; 0.04
ml/dose (application
area [cm2] not stated)
Skin irritation in > 90%
of subjects at 48 h and 96
h post-application (20%
and 39.9%
concentrations); skin
irritation in 54.3% of
subjects at 48 h and in
48.5% of subjects at 96 h
(10% concentration); skin
irritation in 12.9% of
subjects at 48 h and in
13.9% of subjects at 96 h
(5% concentration)
Wahlberg and
Maibach73
20% (in
propanol; pH of
4.3)
16 subjects (10
males, 6 females;
29.5 years)
24 h closed patch (12
mm-diameter Finn
chamber) application
to anterolateral
surface of both upper
arms; dose
volume/cm2 not stated
Erythema and slight
infiltration at 24 h;
occasional slight crusting
at 48 h
Agner and
Serup74
40% , 60%, 70%,
and 80% (in
propanol)
42 male subjects
(mean age of 34
years): 40% (12
subjects), 60% (32
subjects), 70% (32
subjects), and 80%
(28 subjects)
48 h patch (8 mm-
diameter Finn
chamber) application
to volar forearm (30
µl/cm2)
Positive reactions: 2 of 12
subjects (40%
concentration); 20 of 32
subjects (60%); 2 of 32
subjects (70%); and 28 of
28 subjects (80%)
Willis et al.75
20% (in
propanol)
16 subjects (ages not
stated)
24 h closed patch (12
mm-diameter Finn
chamber) application
to anterolateral
surface of both upper
arms; dose
volume/cm2 not stated
Mean irritation score of 2
(moderate positive
reaction) at 24 h; mean
score of 1 (weak positive
reaction) at 96 h
Agner and
Serup76
Table 4. Skin Irritation and Sensitization Studies on Pelargonic Acid, Nonanoate Esters, and Related Chemicals
53
Test Substance Subjects Tested Test Protocol Results References
Pelargonic Acid
80% (in propan-
1-(w/w) 100%
propylene
glycol)
10 male subjects
(mean age of 35
years)
48 h patch (8 mm-
diameter Finn
chamber) application
to volar forearm (30
µl/cm2)
Mild to moderate skin
irritation at 1 h post-
removal
Willis et al.116
20% (in
propanol)
20 subjects (12 males
, 8 females; mean age
of 27.5 years)
24 h closed patch (12
mm-diameter Finn
chamber) application
to flexor side of both
upper arms (0.06
ml/dose; application
area [cm2] not stated)
Skin irritation in all
subjects at 24 h.
Agner and
Serup78
20% (in
propanol)
17 subjects (10
males, 7 females;
mean age of 27
years)
24 h closed patch (12
mm-diameter Finn
chamber) application
to each arm. Seasonal
variation (summer
and winter) in skin
response to
pelargonic acid
evaluated; dose
volume/cm2 not stated
2 subjects with reactions
ranging from score of 0.5
to 2 during winter; 1
subject with reactions
ranging from score of 1 to
2 during summer. No
significant seasonal
variation in skin response
Agner and
Serup117,117
80% (in
propanol, 100%
propylene
glycol)
10 male subjects
(ages not stated)
48 h patch (8 mm-
diameter Finn
chamber) application
to volar forearm (30
µl/cm2)
Most of the irritation
reactions were mild to
moderate at 1 h post-
removal
Willis et al.118
10%,20%, 40%,
and 80% (in
propanol)
152 female subjects
(> 18 years old; 37
were atopic
47 h patch (8 mm-
diameter Finn
chamber) application
to right and left lower
back
Erythema was more
severe at 48 h than at 96 h
at sites on the left and
right lower back (p <
0.001). Except for the
20% concentration (on
left lower back),decreased
erythema with time was
noted at each
concentration
Reiche et al.81
10%, 20%, and
30% (in
propanol)
12 subjects (7 males,
5 females; mean age
of 25.3)
Cumulative skin
irritation test
(ROAT).
Applications (10 min)
made to volar forearm
daily for 5 + 4 days
(no applications on
weekend); 800 µl
53ipette through 20
mm-diameter circular
hole in template
Maximum visual irritation
score of 12 reported for 2
subjects tested with 30%
concentration. Pelargonic
acid considered quite
irritating at all
concentrations tested
Clemmensen et
al.82
Table 4. Skin Irritation and Sensitization Studies on Pelargonic Acid, Nonanoate Esters, and Related Chemicals
54
Test Substance Subjects Tested Test Protocol Results References
Pelargonic Acid
30%, 40%, and
50% (in
propanol)
12 subjects (8
females, 4 males;
mean age of 27)
Cumulative skin
irritation test (Wash
test). Test areas (3 x
5 cm) on volar
forearm washed
(using oral hygiene
sponge) with
respective
concentrations (dose
volume = 4 ml) twice
daily for 12 days.
All subjects received
irritation score of 2 (scale:
0 to 15) for at least one
test concentration.
Clemmesen et
al.82
10% (in
isopropanol)
12 subjects (8 males,
4 females; 18 to 64
years old)
24 h occlusive patch
(10 mm-diameter
Finn chamber)
application (60 µl) to
right and left forearm;
application area [cm2]
not stated
Irritation reactions (scale:
0 to 4+): 2+ (moderate, 5
subjects) and 1+ (mild, 7
subjects )
Suihko and
Serup83
Cetearyl Nonanoate
Undiluted
chemical
52 volunteers (males
and females)
48 h occlusive patch
application (0.2 g) to
upper back;
application area [cm2]
not stated
No skin irritation Symrise
GmbH & Co.
KG36
Neopentyl Glycol Diisononanoate
Undiluted
chemical
52 volunteers (males
and females)
Preceding patch test
procedure;
application area [cm2]
not stated
No skin irritation Symrise
GmbH & Co.
KG 2010c41
PEG-5 Isononanoate
Experimental
formulation
containing 14.5%
PEG-5
isononanoate
53 volunteers 48 h occlusive patch
application (0.2 g) to
upper back;
application area [cm2]
not stated
No skin irritation Symrise
GmbH & Co.
KG42
Ethyl Pelargonate
Concentration
not stated
--- 5 min to 5 h applica-
tion period
No skin irritation Opdyke 29
12% in
petrolatum)
--- 48 h closed patch test No skin irritation Opdyke 29
20% (w/w) in
petrolatum
10 healthy volunteers
(4 males, 6 females;
39 to 70 years old)
24 h occlusive patch
test
No skin irritation Smith et al.84
Table 4. Skin Irritation and Sensitization Studies on Pelargonic Acid, Nonanoate Esters, and Related Chemicals
55
Test Substance Subjects Tested Test Protocol Results References
Provocative Tests – Skin Irritation
Pelargonic Acid
5%, 10%, 20%,
and 100% (in
propanol)
75 allergic contact
dermatitis patients
(males and females;
20 to 70 years old)
48 h patch (Al-test ®
disc) application
(0.04 ml) to upper
back; application area
[cm2] not stated
Skin irritation in 93.9% of
33 women tested and
93.3% of 48 men tested
with 20% concentration
(subjects comprise largest
test group). Additional
results in table 5
Wahlberg and
Maibach119
1%, 5%, 10%,
20%, and 39.9%
(in propanol)
100 hospitalized
patients with skin
disease (54 males, 46
females; ages not
stated)
48 h patch (Al-test ®
disc, saturated with
solution) application
to upper back; dose
volume/cm2 not stated
Irritation reactions (lowest
test concentration
producing a reaction):
1.0% pelargonic acid (1
male; 2 females), 5.0%
(23 males; 9 females),
10.0 % (18 males; 22
females), 20.0% (12
males; 13 females), and
39.9% (all patients)
Wahlberg et
al.120
Skin Irritation and Sensitization
Cetearyl Nonanoate
Undiluted
chemical
106 volunteers
(males and females)
RIPT. 24 h occlusive
patch applications,
0.2 g per patch, to
upper back (induction
and challenge);
application area [cm2]
not stated
No skin irritation or
sensitization
Symrise
GmbH & Co.
KG36
Ethylhexyl Isononanoate
Undiluted
chemical
52 participants
(males and females)
RIPT same as in
preceding study,
except semi-occlusive
patches used
Skin irritation in 10
subjects. No allergic
contact sensitization
Symrise
GmbH & Co.
KG42
Isodecyl Isononanoate
Makeup product
containing
51.35%
101 normal subjects
(18 to 65 years old)
RIPT. 24 h
semiocclusive patch
applications to upper
back (induction and
challenge); dose vol-
ume/cm2 not stated
6 subjects with ± or 1+
reaction during induction.
3 subjects with ± reaction
after challenge. Makeup
product had no dermal
irritation or sensitization
potential.
Clinical
Research
Laboratories,
Inc.87
Table 4. Skin Irritation and Sensitization Studies on Pelargonic Acid, Nonanoate Esters, and Related Chemicals
56
Test Substance Subjects Tested Test Protocol Results References
Isononyl Isononanoate
Lipstick
containing 3.55%
53 subjects RIPT. 24h semi-
occlusive patch
applications,0.2 g per
patch, to back (induc-
tion and challenge);
dose volume/cm2 not
stated
No skin reactivity Consumer
Product
Testing
Company 88
Lipstick
containing 3.13%
97 subjects " No skin reactivity Consumer
Product
Testing
Company 89
Neopentyl Glycol Diisononanoate
Undiluted
chemical
106 volunteers
(males and females)
RIPT. 24 h occlusive
patch applications,
0.2 g per patch, to
upper back (induction
and challenge);
application area [cm2]
not stated
No skin irritation or
sensitization
Symrise
GmbH & Co.
KG41
Predictive Tests - Skin Sensitization
Pelargonic Acid
12% in
petrolatum
25 normal subjects Maximization test No sensitization Opdyke 29
Cetearyl Isononanoate
Liquid makeup
remover
containing 1.5%
25 normal subjects
(18 to 65 years old)
Maximization test No contact allergy KGL, Inc.90
Cholesteryl Nonanoate
Lipstick
containing
20.86%
28 normal subjects
(21 to 57 years old)
Maximization test No contact allergy KGL, Inc.91
Isotridecyl Isononanoate
Facial cream
containing 4.3%
28 normal subjects
(19 to 63 years old)
Maximization test No contact allergy KGL, Inc.92
Isodecyl Isononanoate
Day cream
containing 2.6%
26 normal subjects
(26 to 65 years old)
Maximization test No contact allergy KGL, Inc.93
Table 4. Skin Irritation and Sensitization Studies on Pelargonic Acid, Nonanoate Esters, and Related Chemicals
57
Test Substance Subjects Tested Test Protocol Results References
Isononyl Isononanoate
Eye shadow
containing
24.66%
26 normal subjects
(18 to 65 years old)
Maximization test No contact allergy KGL, Inc.94
PEG-5 Isononanaote
Experimental
formulation
containing 14.5%
PEG-5
isononanoate
53 normal subjects RIPT. Patch
applications, 0.2 g per
occlusive patch, to
upper back (induction
and challenge);
application area [cm2]
not stated
No allergic contact
sensitization
Symrise
GmbH & Co.
KG42
Ethyl Pelargonoate
12% in
petrolatum
25 normal subjects Maximization test No sensitization Opdyke29
Provocative Test – Skin Sensitization
Isotridecyl Alcohol
5% in petrolatum 229 dermatitis
patients (mean age =
39.3 years)
24 h or 48 h patch
applications
No sensitization Geier et al.95
58
Table 5. Patch testing of dermatitis patients with pelargonic acid85
Concentration (%)
Females Males Total
N Positive
(%)
N Positive
(%)
N Positive
(%)
5 25 16.0 13 46.2 38 26.3
10 16 56.3 6 83.3 22 63.6
20 33 93.9 15 93.3 48 93.8
100 6 100 6 100 12 100
61
References
1. Andersen, F. A. Final report on the safety assessment of propylene glycol (PG) dicaprylate, PG
dicaprylate/dicaprate, PG dicocoate, PG dipelargonate, PG isostearate, PG laurate, PG myristate,
PG oleate, PG oleate SE, PG dioleate, PG dicaprate, PG diisostearate, and PG dilaurate.
International Journal of Toxicology. 1999;18:(S2):35-52.
2. Elder, R. L. Final report on the safety assessment of butylene glycol, hexylene glycol, ethoxydiglycol, and
dipropylene glycol. JACT. 1985;4:(5):223-248.
3. Andersen, F. A. Annual review of cosmetic ingredient safety assessments - 2004/2005. International
Journal of Toxicology. 2006;25:(2):10-18.
4. Elder, R. L. Final report on the safety assessment of cetearyl alcohol, cetyl alcohol, isostearyl alcohol,
myristyl alcohol, and behenyl alcohol. JACT. 1988;7:(3):359-413.
5. Andersen, F. A. Annual review of cosmetic ingredient safety assessments - 2002/2003. International
Journal of Toxicology. 2005;24:(S1):1-102.
6. Elder, R. L. Final report on the safety assessment of cholesterol. JACT. 1986;5:(5):491-516.
7. Andersen, F. A. Special report: Reproductive and developmental toxicity of ethylene glycol and its esters.
International Journal of Toxicology. 1999;18:(S2):53-67.
8. Elder, R. L. Final report on the safety assessment of octyl palmitate, cetyl palmitate, and isopropyl
palmitate. JACT. 1982;1:(2):13-35.
9. Andersen, F. A. Annual review of cosmetic ingredient safety assessments - 2002/2003. International
Journal of Toxicology. 2005;24:(S1):1-102.
10. Andersen, F. A. Final report on the safety assessment of PEG-7, -30, -40, -78, and -80 glyceryl cocoate.
International Journal of Toxicology. 1999;18:(S1):33-42.
11. Andersen, F. A. Final report on the safety assessment of PEG (polyethylene glycol)-2, -4, -6, -8, -12, -20, -
32, -75, and -150 dilaurate; PEG-2, -4, -6, -8, -9, -10, -12, -14, -20, -32, -75, -150, and -200
laurate; and PEG-2 laurate SE. International Journal of Toxicology. 2000;19:(S2):29-41.
12. Elder, R. L. Final report on the safety assessment of butyl stearate, cetyl stearate, isobutyl stearate, isocetyl
stearate, isopropyl stearate, myristyl stearate, and octyl stearate. JACT. 1985;4:(5):107-146.
13. Elder, R. L. Final report on the safety assessment of decyl and isodecyl oleates. JACT. 1982;1:(2):85-95.
14. Andersen, F. A. Annual review of cosmetic ingredient safety assessments - 2001/2002. International
Journal of Toxicology. 2003;22:(S1):1-35.
15. Gottschalck, T.E. and Bailey, J.E. International cosmetic ingredient dictionary and handbook. 2008;12th
:
Washington, D.C.:Personal Care Products Council.
16. Symrise GmbH & Co.KG. UV absorbance of isononanoate esters. Unpublished data submitted by the
Personal Care Products Council, February 15, 2010. 2010. 1-5.
17. Scientific and Technical Information Network (STN).Registry file. 9-7-2009. http://stnweb.cas.org.
Accessed 9-7-2009.
62
18. Donnelly, J. R., Abdel-Hamid, M. S., and Jeter, J. L. Application of gas chromatographic retention
properties to the identification of environmental contaminants. Journal of Chromatography.
1993;642:409-415.
19. Nascimento, E. S. P. Cardoso D. R. and Franco D. W. Quantitative ester analysis in Cachaça and distilled
spirits by gas chromatography-mass spectrometry(GC-MS). J.Agric.Food Chem. 2008;56:5488-
5493.
20. Scientific and Technical Information Network (STN).Merck Index file. 2010. http://stnweb.cas.org.
Accessed 4-7-2010.
21. Parchem Trading LTD.Pelargonic Acid. 2010. http://www.parchem.com/chemical-supplier-
distributoer/Pelargonic-Acid-003214.aspx. Accessed 4-7-2010.
22. Food and Drug Administration (FDA). Information supplied to FDA by industry as part of the VCRP. FDA
Database. Washington, D.C.: FDA, 2009.
23. Personal Care Products Council. Use concentration data from industry survey. Unpublished data submitted
by the Personal Care Products Council. 9-17-2009. 1-6.
24. FDA. Title 21 parts 172.515, 173.315, and 178.1010. Washington, D.C.: Government Printing Office,
2009.
25. United States Environmental Protection Agency (EPA). Pesticide Fact Sheet. Pelargonic Acid. NTIS Report
No.PB989-166457. 1998.
26. EPA. Pelargonic acid (217500) fact sheet. 8-20-2009.
27. EPA. Pelargonic acid (nonanoic acid); Exemption from the requirement of a pesticide tolerance. Federal
Register. 2003. 68:7931-7935.
28. EPA. Ammonium nonanoate; notice of filing a pesticide petition to establish a tolerance for a certain
pesticide chyemical in or on food. Federal Register. 2004. 69:12670-12676.
29. Opdyke, D. L. Fragrance raw materials monograph. Pelargonic acid. FoodCosmet Toxicol. 1978;16:839-
841.
30. Scala, R. A. and Burtis, E. G. Acute toxicity of a homologous series of branched-chain primary alcohols.
Am.Ind.Hyg.Assoc.J. 1973;34:(11):493-499.
31. Tanojo, H. and Junginger, H. E. Skin permeation enhancement by fatty acids. J.Disper.Sci.Tech.
1999;%20:(1-2 %1999 P127-138):REF.
32. Kanikkannan, N., Andega, S., Burton, S., Babu, R. J., and Singh, M. Formulation and in vitro evaluation of
transdermal patches of melatonin. Drug Dev.Ind.Pharm. 2004;30:(2):205-212.
33. Stillmeadow Inc. Acute inhalation toxicity study in rats. MRID# 43843503. Unpublished data (on cd-rom)
submitted by the Environmental Protection Agency (EPA) in response to an FOIA request dated
August 31, 2009. 1993.
34. Detwiler-Okabayashi, K. A. and Schaper, M. M. Respiratory effects of a synthetic metalworking fluid and
its components. Arch.Toxicol. 1996;70:195-201.
63
35. The Institute of Environmental Toxicology. JT-101 technical: Acute oral toxicity study in rats. MRID#
43843501. Unpublished data (on cd-rom) submiotted by the Environmental Protection Agency in
response tio an FOIA request dated August 31, 2009. 1993.
36. Symrise GmbH & Co.KG. Summary of human safety studies of SymMollient S (cetearyl nonanoate).
Unpublished data submitted by the Personal Care Products Council, February 15, 2010. 2010. 1-
10.
37. Evonik Industries. Summary of product data, with reference to toxicology and ecology, on Tegosoft CI
(cetearyl isononanoate). Unpublished data submitted by the Personal Care Products Council,
October 23, 2009. 2008. 1-1.
38. Evonik Industries. Summary of product data, with reference to toxicology and ecology, on Tegosoft INI
(isononyl isononanoate). Unpublished data submitted by the Personal Care Products Council,
October 23, 2009. 2009. 1-1.
39. Consumer Product Testing. Primary dermal irritation (rabbit), primary ocular irritation (rabbit), acute oral
toxicity (rat) of ethyl pelargonate. Experiment reference no. 79205. Unpublished data submitted
by the Personal Care Products Council, January 25, 2010. 1979. 1-4.
40. Guilian, W. and Naibin, B. Structure-activity relationships for rat and mouse LD50 of miscellaneous
alcohols. Chemosphere. 1998;36:1475-1483.
41. Symrise GmbH & Co.KG. Summary of human safety studies on of SymMollient L (neopentyl glycol
diisononanoate). 2010. 1-9.
42. Symrise GmbH & Co.KG. Summary of human safety studies of PEG-5 isononanoate. Unpublished data
submitted by the Personal Care Products Council, February 15, 2010. 2010. 1-12.
43. Ministry of Health and Welfare (MHW), Japan. Unpublished Reports on Combined Repeated Dose and
Reproductive/Developmental Toxicity Screening Test and Mutagenicity Test Conducted by the
Ministry of Health and Welfare (MHW), Japan. In: OECD Screening Information Data Sets
(SIDS). Neopentyl Glycol. OECD. 1993.
http://www.inchem.org/documents/sids/sids/126307.pdf.
44. The Institute of Environmental Toxicology. Acute dermal toxicity study in rats. MRID#
43843502.Unpublished data (on cd-rom) submitted by the Environmental Protectiion Agency in
response to an FOIA request dated August 31, 2009. 1993.
45. Oro, L and Wretlind, A. Pharmacological effects of fatty acids, triolein and cottonseed oil. Acta Pharmacol
Toxicol. 1961;18:141-152.
46. Hazleton Laboratories America, Inc. Initial submission: : Maternal tolerance study in rats with cover letter
dated 102792. NTIS Report No.OTS0546549. 1981.
47. Hazleton Laboratories America, Inc. Initial submission: 28-day feeding study of nonanoic acid in rats with
attachments and cover letter dated 080592. NTIS Report No.OTS0542102. 1987.
48. Stillmeadow Inc. Range-finding for a 90-day rat oral toxcity (diet). Final Report. MRID# 43843507.
Unpublished data (on cd-rom) submitted by the Environmental Protection Agency in response to
an FOIA request dated Autust 31, 2009. 1995.
49. Rhodes, C. Soames T. Stonard M. D. Simpson M. G. Vernall A. J. and Elcome C. R. The absence of
testicular atrophy and in vivo and in vitro effects on hepatocyte morphology and peroxisomal
64
enzyme activities in male rats following the adminstration of several alkanols. Toxicology Letters.
1984;21:103-109.
50. Biodynamics, Inc. A 28-day dermal toxicity study in rabbits with cover letter dated 102792. NTIS Report
No.OTS0546557. 1981.
51. Montelius, J., Wahlkvist, H., Boman, A., and Wahlberg, J. E. Murine local lymph node assay for predictive
testing of allergenicity: two irritants caused significant proliferation. Acta Derm.Venereol.
1998;78:(6):433-437.
52. STN.Registry of toxic effects of chemical substances (RTECS) file. 9-7-2009. http://stneasy.cas.org.
53. Hazleton Wisconsin Inc. Primary eye irritation study of pelargonic acid in rabbits. MRID# 43843504.
Unpublished data (on cd-rom) submitted by the Environmental Protection Agency in response to
an FOIA request dated August 31, 2009. 1993.
54. Hazleton Wisconsin Inc. Primay dermal irritation study of pelargonic acid in rabbits (EPA guidelines).
MRID# 43843505. Unpublished data (on cd-rom) submitted by the Environmental Protection
Agency in respnose to an FOIA request dated August 31, 2009. 1993.
55. Ahlfors, E. E. and Larsson, A. Chemically induced inflammation in rat oral mucosa. Scand.J.Dent.Res.
1988;96:(5):428-434.
56. Hazleton Wisconsin Inc. Dermal sensitization study of pelargonic acid in guinea pigs-closed patch
technique (EPA guidelines). MRID# 43843506. Unpublished data (on cd-rom) submitted by the
Environmental Protection Agency in response to an FOIA request dated August 31, 200. 1993.
57. Sikorski, E. E., Gerberick, G. F., Ryan, C. A., Miller, C. M., and Ridder, G. M. Phenotypic Analysis of
Lymphocyte Subpopulations in Lymph Nodes Draining the Ear Following Exposure to Contact
Allergens and Irritants. Fundamental.and Applied.Toxicology. 1996;34:(1).
58. Kimber, I. and Basketter D. A. The murine local lymph node assay: A commentary on collaborative studies
and new directions. Food Chem Toxicol. 1992;30:165-169.
59. Pistoor, F. Hm, Rambukkana, A., Kroezen, M., Lepoittevin, J.-P., Bos, J. D., Kapsenberg, M. L., and Das,
P. K. Novel predictive assay for contact allergens using human skin explant cultures.
American.Journal of Pathology. 1996;149:(1):337-343.
60. Woolhiser, M. R., Hayes, B. B., and Meade, B. J. A combined murine local lymph node and irritancy assay
to predict sensitization and irritancy potential of chemicals. Toxicology Methods. 1998;8:(4):245-
256.
61. Hazleton Laboratories America, Inc. Teratology screen in rats. Pelargonic acid. Final report. NTIS Report
No.OTS0545226. 1982.
62. Hellwig, J and Jäckh, R. Differential prenatal toxicity of one straight-chain and five branched-chain
primary alcohols in rats. Food Chem.Toxicol. 1997;35:(5):489-500.
63. Hazleton Washington, Inc. Mutagenicity test on pelargonic acid (technical grade) in the
Salmonella/mammalian-microsome reverse mutation assay (Ames test). MRID# 43603703.
Unpublished data (on cd-rom) submitted by the Environmental Protection Agency (EPA) in
respoonse to an FOIA request dated August 31, 2009. 1993.
64. Hazleton Washington Inc. Mutagenicity test on pelargonic acid (technical grade) in the L5178Y TK+/-
mouse lymphoma forward mutation assay with a confirmatory assay. MRID# 43603701.
65
Unpublished data (on cd-rom) submitted by the Environmental Protection Agency in response to
an FOIA request dated August 31, 2009. 1993.
65. Hazleton Washington Inc. Mutagenicity test on n-pelargonic acid. In vivo mouse micronucleus assay.
MRID# 43603702. Unpublished data (cd-rom) submitted by EPA in response to an FOIA request
dated August 31, 2009. 1993.
66. National Toxicology Program (NTP).Testing status: pelagonic acid M070024. Genetic toxicology -
Salmonella (A341272) completed. 9-7-2009. http://ntp-
apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=salmonella.salmonellaData&stu...
67. Symrise GmbH & Co.KG. Summary of human safety studies of Dragoxat 89 (ethylhexyl isononanoate).
Unpublished data submitted by the Personal Care Products Council, February 15, 2010. 2010. 1-4.
68. Kusakabe, H, Yamakage, K, Wakuri, S, Sasaki, K, Nakagawa, Y, Watanabe, M, Hayashi, M, Sofuni, T.,
Ono, H., and and Tanaka, N. Relevance of chemical structure and cytotoxicity to the induction of
chromosome aberrations based on the testing results of 98 high production volume industrial
chemicals. Mutation Research. 2002;517:187-198.
69. Renner, H. W. The anticlastogenic potential of fatty acid methyl esters. Mutat Res. 1986;172:265-269.
70. University of Cincinnati Medical Center's Kettering Laboratory. Initial submission: Chronic mouse dermal
toxicity study of a mixture of valeric acid, heptanoic acid, pelargonic acid, and tripropylene glycol
dicaprylate w/cover letter dated 102792. NTIS Report No.OTS0571597. 1985.
71. Nishikawa, Y. Okabe M. Yoshimoto K. Kurono G. and Fukuoka F. Chemical and biochemical studies on
carbohydrate esters. II. Antitumor activity of saturated fatty acids and their ester derivatives
against Ehrlich ascites carcinoma. Chem Pharm Bull. 1976;24:387-393.
72. Stillman, M. A. Maibach H. I. and Shalita A. R. Relative irritancy of free fatty acids of different chain
length. Contact Dermatitis. 1975;1:65-69.
73. Wahlberg, J. E. and Maibach, H. I. Nonanoic acid irritation: A positive control at routine patch testing?
Contact Dermatitis. 1980;6:(2):128-130.
74. Agner, T. and Serup, J. Skin reactions to irritants assessed by polysulfide rubber replica. Contact
Dermatitis. 1987;17:(4):205-211.
75. Willis, C. M., Stephens, J. M., and Wilkinson, J. D. Experimentally-induced irritant contact dermatitis.
Determination of optimum irritant concentrations. Contact Dermatitis. 1988;18:(1):20-24.
76. Agner, T. and Serup, J. Contact thermography for assessment of skin damage due to experimental irritants.
Acta Derm.Venereol. 1988;68:(3):192-195.
77. Willis, C. M., Stephens, C. J., and Wilkinson, J. D. Epidermal damage induced by irritants in man: light
and electron microscopic study. J.Invest.Dermatol. 1989;93:(Nov %1989 P695-699):REF.
78. Agner, T. and Serup, J. Skin reactions to irritants assessed by non-invasive bioengineering methods.
Contact Dermatitis. 1989;%20:(5):352-359.
79. Agner, T. and Serup, J. Seasonal variation of skin resistance to irritants. Br.J.Dermatol. 1989;121:(3):323-
328.
66
80. Willis, C. M., Stephens, C. Jm, and Wilkinson, J. D. Differential effects of structurally unrelated chemical
irritants on the density and morphology of epidermal CD1 positive cells. J.Invest Dermatol.
1990;95:(6):711-716.
81. Reiche, L., Willis, C., Wilkinson, J., Shaw, S., and de, Lacharriere O. Clinical morphology of sodium
lauryl sulfate (SLS) and nonanoic acid (NAA) irritant patch test reactions at 48 h and 96 h in 152
subjects. Contact Dermatitis. 1998;39:(5):240-243.
82. Clemmensen, A., Andersen, F., Petersen, T. K., Kalden, H., Melgaard, A., and Andersen, K. E. The irritant
potential of n-propanol (nonanoic acid vehicle) in cumulative skin irritation: a validation study of
two different human in vivo test models. Skin Res.Technol. 2008;14:(3):277-286.
83. Suihko, C. and Serup, J. Fluorescence confocal laser scanning microscopy for in vivo imaging of epidermal
reactions to two experimental irritants. Skin Res.Technol. 2008;14:(4):498-503.
84. Smith, J. S., Macina, O. T, Sussman, N. B., Karol, M. H., and and Maibach, H. I. Experimental validation
of a structure-activity relationship model of skin irritation by esters. Quant.Struct-Act.Relat.
2000;19:467-474.
85. Wahlberg, J. E. and Maibach, H. I. Nonanoic acid irritation - a positive control at routine patch testing?
Contact Dermatitis. 1980;6:(2):128-130.
86. Wahlberg, J. E., Wrangsjo, K., and Hietasalo, A. Skin irritancy from nonanoic acid. Contact Dermatitis.
1985;13:(4):266-269.
87. Clinical Research laboratories Inc. Repeated insult patch test of a makeup containing 51.35% isodecyl
isononanoate. Unpublished data submitted by the Personal Care Products Council, December 17,
2009. 2009. 1-13.
88. Consumer Product Testing Company. Summary of an HRIPT of a lipstick containing 3.552% isononyl
isononanoate. Unpublished data submitted by the Personal Care Products Council, November 30,
2009. 2007.
89. Consumer Product Testing Company. Summary of an HRIPT of a lipstick containing 3.128% isononyl
isononanoate. Unpublished data submitted by the Personal Care Products Council, November 30,
2009. 2007.
90. KGL Inc. An evaluation of the contact-sensitization potential of a topical coded product in human skin by
means of the maximization assay (product contained 1.5% cetearyl isononanoate). KGL protocol
6793. Unpublished data submitted by the Personal Care Products Council, December 17, 2009.
2009. 1-10.
91. KGL Inc. An evaluation of the contact-sensitization potential of a topical coded product in human skin by
means of the maximization assay (product containied 20.86% cholesteryl nonanoate). KGL
protocol 5543. Unpublished data submitted by the Personal Care Products Council, December 17,
2009. 2004. 1-10.
92. KGL Inc. An evaluation of the contact-sensitization potential of a topical coded product in human skin by
means of the maximization assay (product contained 4.3% isotridecyl isononanoate). KGL
protocol 5696. Unpublished data submitted by the Personal Care Products Council, December 17,
2009. 2004. 1-11.
93. KGL Inc. An evaluation of the contact-sensitization potential of a topical coded product in human skin by
means of the maximization assay (product contained 2.6% isodecyl isononanoate). KGL protocol
67
6705. Unpublished submitted by the Personal Care Products Council, December 17, 2009. 2009.
1-10.
94. KGL Inc. An evaluatioin of the contact-sensitization potential of a topical coded product in human skin by
means of the maximization assay (product contained 24.66% isononyl isononanoate). KGL
protocol 6793. Unpublished data submitted by the Personal Care Products Council, December 17,
2009. 2008. 1-10.
95. Geier, J, Lessmann, H., Frosch, P. J., Pirker, C, Koch, P., Aschoff, R., Richter, G., Becker, D., Eckert, C.,
Uter, W., Schnuch, A., and and Fuchs, T. Patch testing with components of water-bsased
metalworking fluids. Contact Dermatitis. 2003;49:85-90.
96. Willis, C. M., Stephens, C. Jm, and Wilkinson, J. D. Differential effects of structurally unrelated chemical
irritants on the density of proliferating keratinocytes in 48 h patch test reactions. J.Invest
Dermatol. 1992;99:(4):449-453.
97. Forsey, R. J., Shahidullah, H., Sands, C., McVittie, E., Aldridge, R. D., Hunter, J. A., and Howie, S. E.
Epidermal Langerhans cell apoptosis is induced in vivo by nonanoic acid but not by sodium lauryl
sulphate. Br.J.Dermatol. 1998;139:(3):453-461.
98. Lindberg, M., Farm, G., and Scheynius, A. Differential effects of sodium lauryl sulphate and non-anoic
acid on the expression of CD1a and ICAM-1 in human epidermis. Acta Derm.Venereol.
1991;71:(5):384-388.
99. Mathias, C. Gt, Maibach, H. I., and Conant, M. A. Perioral leukoderma simulating vitiligo from use of a
toothpaste containing cinnamic aldehyde. Arch.Dermatol. 1980;116:(10):1172-1173.
100. Le Coz, C. J. and Bressieux, A. Allergic contact dermatitis from cetearyl isononanoate. Contact Dermatitis.
2003;48:(6):343-343.
101. Goossens, A., Verbruggen, K., Cattaert, N., and Boey, L. New cosmetic allergens: isononyl isononanoate
and trioleyl phosphate. Contact Dermatitis. 2008;59:(5):320-321.
102. Lewis, R. J. Dangerous Properties of Industrial Materials. 10th ed. New York: Wiley-Interscience, 2000.
103. Committeee of Revision of the United States Pharmacopeial Convention. The United States Pharmacopeia.
26th ed. Rockville, MD: United States Pharmacopoeial Convention, Inc., 2003.
104. Advanced Chemistry Development (ACD) Labs.ACD Labs calculated values. In: Scienific and Technical
Information Network's Registry file. 2010. http://stnweb.cas.org. Accessed 4-9-2010.
105. Evonik Industries. Material safety data sheet on Tegosoft CI (cetearyl isononanoate). Unpublished data
submitted by the Personal Care Products Council, October 23, 2009. 2007. 1-8.
106. Evonik Industries. Product specification on Tegosoft CI (cetearyl isononanoate). Unpublished data
submitted by the Personal Care Products Council, October 23, 2009. 2008. 1-1.
107. Evonik Industries. Further product information on Tegosoft CI (cetearyl isononanoate). Unpublished data
submitted by the Personal Care Poducts Council, October 23, 2009. 1999. 1-3.
108. Evonik Industries. Product data record on Tegosoft CI (cetearyl isononanoate). Unpublished data submitted
by the Personal Care Products Council, October 23, 2009. 2008. 1-3.
109. Nikitakis, J. M. and McEwen, G. N. Jr. CTFA Compendium of Cosmetic Ingredient Composition -
Specifications. Washington, D.C.: CTFA, 1990.
68
110. Evonik Industries. Material safety data sheet on Tegosoft INI (isononyl isononanoate). Unpublished data
submitted by the Personal Care Products Council, October 23, 2009. 2009. 1-8.
111. Evonik Industries. Product specification on Tegosoft INI (isononyl isononanoate). Unpublished data
submitted by the Personal Care Products Council, October 23, 2009. 2008. 1-1.
112. Evonik Industries. Product data record on Tegosoft INI (isononyl isononanoate). Unpublished data
submitted by the Personal Care Products Council, October 23, 2009. 2009. 1-3.
113. SRC.InteractiveLogKow (KowWin) Demo. 2010. http://www.srcinc.com/what-we-
do/databaseforms.aspx?id=385. Accessed 3-3-2010.
114. Scientific and Technical Information Network (STN.Beilstein file. 2010. http://stnweb.cas.org. Accessed
1-11-0010.
115. National Institute for Occupational Safety and Health (NIOSH). International Chemical Safety Cards.
Neopentyl glycol. 2010. 1-3.
116. Willis, C. M., Stephens, C. J. M., and Wilkinson, J. D. Epidermal Damage Induced by Irritants in Man: A
Light and Electron Microscopic Study. Journal of Investigative.Dermatology. 1989;93:(5).
117. Agner, T. and Serup, J. Seasonal variation of skin resistance to irritants. Br.J.Dermatol. 1989;121:(3):323-
328.
118. Willis, C. M., Stephens, C. J., and Wilkinson, J. D. Differential effects of structurally unrelated chemical
irritants on the density and morphology of epidermal CD1+ cells. J.Invest Dermatol.
1990;95:(6):711-716.
119. Wahlberg, J. E., Wrangsjo, K., and Hietasalo, A. Skin irritancy from nonanoic-acid. Contact Dermatitis.
1985;13:(4):266-269.
120. Wahlberg, J. E., Wrangsjo, K., and Hietasalo, A. Skin Irritancy From Nonanoic Acid. Contact Dermatitis.
1985;13:(4):Hospitalized-acid.